AU2018305614B2 - Piperazine heteroaryl derivative, preparation method therefor and use of same in medicine - Google Patents

Piperazine heteroaryl derivative, preparation method therefor and use of same in medicine Download PDF

Info

Publication number
AU2018305614B2
AU2018305614B2 AU2018305614A AU2018305614A AU2018305614B2 AU 2018305614 B2 AU2018305614 B2 AU 2018305614B2 AU 2018305614 A AU2018305614 A AU 2018305614A AU 2018305614 A AU2018305614 A AU 2018305614A AU 2018305614 B2 AU2018305614 B2 AU 2018305614B2
Authority
AU
Australia
Prior art keywords
compound
formula
alkyl
group
heterocyclyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
AU2018305614A
Other versions
AU2018305614A1 (en
Inventor
Yang Chen
Feng He
Wei He
Xin Li
Weikang Tao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
Original Assignee
Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Hengrui Medicine Co Ltd, Shanghai Hengrui Pharmaceutical Co Ltd filed Critical Jiangsu Hengrui Medicine Co Ltd
Publication of AU2018305614A1 publication Critical patent/AU2018305614A1/en
Application granted granted Critical
Publication of AU2018305614B2 publication Critical patent/AU2018305614B2/en
Ceased legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Epidemiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyridine Compounds (AREA)

Abstract

The present invention relates to a piperazine heteroaryl derivative, a preparation method therefor and the use of same in medicine. In particular, the present invention relates to the piperazine heteroaryl derivative as shown in the general formula (I), a preparation method therefor, a pharmaceutical composition comprising the derivative, and the use of same as a capsid protein inhibitor, in particular in the prevention and/or treatment of diseases such as hepatitis B, influenza, herpes, AIDS, etc. The definitions of each group in the general formula (I) are the same as those defined in the description.

Description

PIPERAZINE HETEROARYL DERIVATIVE, PREPARATION METHOD THEREFOR AND USE OF SAME IN MEDICINE FIELD OF THE INVENTION
The present invention belongs to the field of medicine, and relates to a piperazinoheteroaryl derivative, a method for preparing the same, and a use thereof in medicine. In particular, the present invention relates to a piperazinoheteroaryl derivative of formula (I), a method for preparing the same, a pharmaceutical composition comprising the same, and a use thereof as a capsid protein inhibitor, particularly in preventing and/or treating diseases such as hepatitis B, influenza, herpes and AIDS.
BACKGROUND OF THE INVENTION
Chronic hepatitis B virus (HBV) infection is already a global health issue. According to the World Health Organization, about 2 billion people worldwide had been infected with HBV, of which 240 million are chronic HBV-infected people. About 650,000 people die each year from liver failure, liver cirrhosis and hepatocellular carcinoma (HCC) caused by HBV infection. 30% of liver cirrhosis patients and 45% of HCC patients are caused by HBV infection worldwide. Although prophylactic HBV vaccines can be used, chronic HBV infection has become a worldwide medical issue due to the lack of effective drugs. At present, there are mainly two classes of drugs for treating chronic HBV infection: alpha-interferon formulations (such as pegylated alpha-interferon) and nucleoside analogues that inhibit HBV DNA polymerase (such as lamivudine, adefovir and the like). However, the interferon formulations have severe side effects and poor tolerance, and only a small percentage of patients can have a sustained clinical response to interferon therapy (Lancet. 2005 Jan 8-14;365(9454): 123-9.; N Engl J Med. 2005 Jun 30; 352(26):2682-95.; Hepatology. 2009 May; 49(5 Suppl): S103-11). As a competitive inhibitor of reverse transcriptase, nucleoside analog drugs exert an antiviral effect by blocking the synthesis of HBV DNA strands. However, existing nucleoside analog drugs also have issues such as inducing the reverse transcriptase to produce drug-resistant mutations and a poor efficacy against drug-resistant strains. Moreover, these drugs are often difficult to completely eliminate HBV infection, even if they are administrated for a long time; once the drug is withdrawn, there might be a serious rebound phenomenon, thus lifelong medication is needed (Hepatology. 2009 May;49(5 Suppl):S112-21). Therefore, there is an urgent need to develop a novel, safe and effective drug for chronic hepatitis B. The low cure rate of chronic HBV infection is closely related to the characteristics of hepatitis B virus (HBV). HBV is an enveloped, partially double-stranded DNA (dsDNA) virus of Hepadnaviridae family. The outermost layer of mature HBV viral particles is an envelope protein, encapsulated by the HBV nucleocapsid. The nucleocapsid is also called core particle, and is composed of capsid protein, HBV relaxed circular DNA (rcDNA) and HBV reverse transcriptase bound to the 5' end of the negative strand of rcDNA. Upon infection, rcDNA is converted to covalently closed circle DNA (cccDNA) in the host cell nucleus as a replication template of HBV. An important step during HBV replication is the encapsidation. Pregenomic RNA (pgRNA) transcribed from cccDNA needs to be encapsulated in the capsid protein together with HBV reverse transcriptase to complete the assembly step, thereby triggering subsequent reverse transcription. The HBV reverse transcriptase and pgRNA need to be properly encapsulated by the capsid protein before reverse transcription. Therefore, blocking capsid protein assembly or accelerating capsid protein degradation can block the capsid assembly process, thereby affecting viral replication. Moreover, the N-terminal 149 amino acid residues (Cp149), which constitute the core protein dimerization motif and assembly domain, have no human protein homologous sequences. Therefore, the capsid protein assembly inhibitor is considered as a new target for anti-hepatitis B drug development. Due to the different mechanism with conventional antiviral drugs, the capsid protein inhibitor can be combined with a DNA polymerase inhibitor to synergistically inhibit HBV replication and prevent drug resistance, providing a safer and more effective treatment for chronic hepatitis B infection. At present, there are mainly two classes of capsid protein inhibitors: heteroaryl dihydropyrimidines (HAPs) and phenylacrylamides, such as GLS-4, NVR-3778 and the like. Related patent applications include W02001068642, W02014029193, W02015011281, W02016016196, W02017076791, W02016113273 and the like. However, most of the compounds directed to this target are in clinical research, and there are no marketed drugs. Therefore, there is still a need to continuously develop capsid protein inhibitors to improve the safety and effectiveness of the drugs, and to overcome the problem of chronic HBV infection at an early date. The capsid protein inhibitor interferes with the normal assembly of capsid protein by binding to the assembly domain of the core protein dimerization motif, thereby affecting HBV replication. Therefore, a good pharmacokinetic absorption and a high bioavailability (which can result in higher concentration of the compound in the body) can more effectively block HBV replication. The present invention provides a novel structure of a capsid protein inhibitor of formula (I), wherein the substituent on the heteroaryl is an acylamino group, and the amino group in the acylamino group is preferably a secondary amino group. The present invention designs a comparative example (Example 59) that corresponds to the compound of formula (I), in the NRR 2 moiety, R1 and R 2 together with the nitrogen atom forms a ring having a tertiary amino group. The comparative example demonstrates that when the amino group in the acylamino group on the heteroaryl is a secondary amino group, the compound exhibits a significantly improved biological activity, and has an obvious inhibition effect on the normal assembly of HBV capsid protein, a good pharmacokinetic absorption and a high bioavailability. Meanwhile, the novel structure of the compound of formula (I) has no or little effect on the in vitro proliferation inhibition of HepG2 cells , and shows a good safety.
SUMMARY OF THE INVENTION
The present disclosure provides a compound of formula (I): R2 0 0 N/
NN %R1 (RA4 (R S 3 N
/ (R)
(1) or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: ring A is aryl or heteroaryl; Y is N or CR; Q is N or CH; R 1 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted by one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6 , -C(O)R 6, -C(O)OR 6 and -S(O)mR 6; R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted by one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6 , -C(O)R 6, -C(O)OR 6 and -S(O)mR 6; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 ,
-C(O)OR6 and -S(O)mR 6 ; each R4 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 ,
-C(O)OR6 and -S(O)mR 6 ; R 5 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 6 is selected from the group consisting of hydrogen, alkyl, haloalkyl, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is 0, 1, 2 or 3; m is 0, 1 or 2; and s is 0, 1, 2, 3 or 4. In a preferred embodiment of the present invention, the compound of formula (I) according to the present invention is a compound of formula (II): O H 0 Nll A ),N 'R1 ( e H I Y N"// (R
) (II) wherein: ring A, Y, Q, R1 , R 3 , R 4 , s and n are as defined in formula (I). In another preferred embodiment of the present invention, the compound of formula (I) according to the present invention is a compound of formula (III), formula (IV), formula (V) or formula (VI): 0 H 0 H 0 N 0 N A R1"' A NN R1
HR (R )(R ) OH OHH (III) (IV)
03 R( N
(Rn)n (R 3 )n
(V) (VI) wherein: ring A, R1 ,R 3 , R4 , sand nare as defined in formula (I). In another preferred embodiment of the present invention, in the compound of formula (I) according to the present invention, ring Ais phenyl or pyridyl. In another preferred embodiment of the present invention, the compound of formula (I) according to the present invention is acompound of formula (VII), formula (VIII), formula (IX) or formula (X):
O H O,"0H 4 0 N 0 (R ) NRN 4 R (R ) N N R1 H, R N N H R3 N' H N H N (R v11 ( VIII (R 3)n (R3 )n
(VI) (Vil)
0 N 0 N N N N JRu-N ~~ H LN ,N HN 1 (R 33)1--- N(R ) nR n
(IX) (X) wherein: G is C or N; and R 1, R 3 , R 4 , s and n are as defined in formula (I). In another preferred embodiment of the present invention, in the compound of formula (I) according to the present invention, R1 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl and aryl, wherein the alkyl, cycloalkyl, heterocyclyl and aryl are optionally further substituted by one or more substituents selected from the group consisting of halogen, alkyl, alkoxy and hydroxy. In another preferred embodiment of the present invention, the compound of formula (I) according to the present invention is a compound of formula (VII-A), formula (VIII-A), formula (IX-A) or formula (X-A): 0 H O H
(R4)s NR)SK G, 0 N R R9 (R4)s N N R N N -1
3 R3 N N R NN
(VII-A) (VIII-A)
(R 4)S N N N R9 (R 4)s NN R9 H N R8 H N! R8 R3 N R.. R3 1
(IX-A) (X-A) wherein: G is C or N; R 8 is alkyl, preferably methyl; R 9 is alkyl, wherein the alkyl is optionally further substituted by one or more halogen; and R 3, R 4 , s and n are as defined in formula (I). In another preferred embodiment of the present invention, in the compound of formula (I) according to the present invention, R 3 is hydrogen or alkyl.
In another preferred embodiment of the present invention, in the compound of formula (I) according to the present invention, R 4 is selected from the group consisting of hydrogen, halogen, haloalkyl and cyano. Typical compounds of formula (I) include, but are not limited to: Example Structure and name of the compound No. F F O H F
F N N N H NN 1
(R)-N7 -(3,4,5-Trifluorophenyl)-N-(1,1,1-trifluoropropan-2-yl)-5,6-dihydr oimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide F O H F
F N N F H NN'
2 2
(R)-N5-(3,4-Difluorophenyl)-N 3-(1,1,1-trifluoropropan-2-yl)-6,7-dihydrop
yrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide F O H F
N N N F N H NN 3N 3
(R)-N7-(3-Cyano-4-fluorophenyl)-N 1 -(1,1,1-trifluoropropan-2-yl)-5,6-dihy droimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide F F O H F
F N N N F H NN' 4 4
(R)-N5-(3,4,5-Trifluorophenyl)-N 3 -(1,1,1-trifluoropropan-2-yl)-6,7-dihydr
opyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide F OH F
F:O N N N F H NJN 5 5
(R)-N7 -(3,4-Difluorophenyl)-N-(1,1,1-trifluoropropan-2-yl)-5,6-dihydroi midazo[1,5-a]pyrazine-1,7(811)-dicarboxamide F O H F 0 N F F N N N F H . N 66 6 (S)-N7-(3,4-Difluorophenyl)-6-methyl-N-((R)-1,1,1-trifluoropropan-2-yl) 5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide
F O H F F N N ,N F H ,. N
' 77 7
(S)-N5-(3,4-Difluorophenyl)-6-methyl-N 3-((R)-1,1,1-trifluoropropan-2-yl) 6,7-dihydropyrazolo[ 1,5-a]pyrazine-3,5(4H)-dicarboxamide
0 N F N N H , N_
' 8 8
(S)-N3-(Tert-butyl)-N5-(3,4-difluorophenyl)-6-methyl-6,7-dihydropyrazolo
[1,5-a]pyrazine-3,5(4H)-dicarboxamide8 F 0 0 H F
N NN F H N~
9
(R)-N5-(3-Cyano-4-fluorophenyl)-N 3-(1,1,1-trifluoropropan-2-yl)-6,7-dihy
dropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide9 F
ON N F
F O N 10 3 (S)-N -(Tert-butyl)-6-methyl-N5-(3,4,5-trifluorophenyl)-6,7-dihydropyrazo lo[1,5-a]pyrazine-3,5(4H)-dicarboxamide10 O 0H F
N N F
11
(S)-N7-(3-Cyano-4-fluorophenyl)-6-methyl-N 1 -((R)-1,1,1-trifluoropropan 2-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide11 O NH F~aN Hl5z ,. N r
12 12
(S)-N-(Tert-butyl)-N 7 -(3,4-difluorophenyl)-6-methyl-5,6-dihydroimidazo[ 1,5-a]pyrazine-1,7(8H)-dicarboxamide12
F
F N N 13 H .. N
13
(S)-6-Methyl-N 1 -(3-methyloxetan-3-yl)-N 7 -(3,4,5-trifluorophenyl)-5,6-dih ydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide13 F
F N N- NK) H /0 14 ,, ,N'N
14
(S)-6-Methyl-N 3-(3-methyloxetan-3-yl)-N 5 -(3,4,5-trifluorophenyl)-6,7-dih ydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide14 F 0 H F
1 N F
15
(S)-N5-(3-Cyano-4-fluorophenyl)-6-methyl-N 3-((R)-1,1,1-trifluoropropan 2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide15 F O H F N
F N N 16 H . N 16
(S)-N5-(2,6-Difluoropyridin-4-yl)-6-methyl-N 3-((R)-1,1,1-trifluoropropan 2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide16 F F N NF
H N'N, 17 N 17
(R)-N5-(3,4,5-Trifluorophenyl)-N 3 -(1,1,1-trifluoropropan-2-yl)-6,7-dihydr o-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide17 F F& 0 H F NF F N' N 18H N,//
18
(S)-6-Methyl-N 7-(3,4,5-trifluorophenyl)-N 1 -((R)-1,1,1-trifluoropropan-2-yl )-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide18
F F 0OH F /N
F NN H'N O 19 19
N 3-(3-Methyloxetan-3-yl)-N 5 -(3,4,5-trifluorophenyl)-6,7-dihydropyrazolo 1,5-a]pyrazine-3,5(4H)-dicarboxamide19 F O H F 0 NrkF
F N NKN N F H N
20
(S)-N7 -(2,6-Difluoropyridin-4-yl)-6-methyl-N-((R)-1,1,1-trifluoropropan 2-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 20 F F O H 0 N
FKNN N
21 H N 21
(R)-N3 -(Sec-butyl)-N5-(3,4,5-trifluorophenyl)-6,7-dihydropyrazolo[1,5-a]p yrazine-3,5(4H)-dicarboxamide21 F0 H
F N N H/ , N 22 22
(S)-N3-((R)-Sec-butyl)-N5-(3,4-difluorophenyl)-6-methyl-6,7-dihydropyraz olo[1,5-a]pyrazine-3,5(4H)-dicarboxamide22 F OH
F~IaN 0N -N H . N'N 23 23
(S)-N5 -(3,4-Difluorophenyl)-N 3-isopropyl-6-methyl-6,7-dihydropyrazolo[1 ,5-a]pyrazine-3,5(4H)-dicarboxamide23 F 0 H
F NN HN 24 24
(S)-N5-(3,4-Difluorophenyl)-N 3 -(1-methoxy-2-methylpropan-2-yl)-6-meth yl-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide24
0 H F N 0 N _ -F F N N F PH
/ ci ,.. N'N 25
(S)-N-(3-Chloro-2-fluoropyridin-4-yl)-6-methyl-N 3 -((R)-1,1,1-trifluoropr opan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide25 F F 0 H
F N N N
26 H N
26
(R)-N-(Sec-butyl)-N 7-(3,4,5-trifluorophenyl)-5,6-dihydroimidazo[1,5-a]p yrazine-1,7(8H)-dicarboxamide26 F F 0 0OH
27 F N HN,j N - N 7 27
(S)-N3-(Tetrahydrofuran-3-yl)-N 5-(3,4,5-trifluorophenyl)-6,7-dihydropyraz olo[1,5-a]pyrazine-3,5(4H)-dicarboxamide27 F0 H F~. 0 N F N NOH
28 H N'N 28
(S)-N5-(3,4-Difluorophenyl)-N 3 -(1-hydroxy-2-methylpropan-2-yl)-6-meth yl-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide28 F N N F
H 29 F 29 29
(R)-N5-(3,4-Difluorophenyl)-2-methyl-N 3-(1,1,1-trifluoropropan-2-yl)-6,7 dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide29 F F0 H
F N N H NN 30
Nl-(3-Methyloxetan-3-yl)-N 7-(3,4,5-trifluorophenyl)-5,6-dihydroimidazo[ 1,5-a]pyrazine-1,7(8H)-dicarboxamide30
H NOH F
31 H 31
(R)-N5-(3,4-Difluorophenyl)-N 3-(1,1,1-trifluoropropan-2-yl)-6,7-dihydro-[
1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide31 F 0 H F
F N N F
32H N
32
(R)-N7 -(2,6-Difluoropyridin-4-yl)-N 1 -(1,1,1-trifluoropropan-2-yl)-5,6-dihy droimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide32 F F O H F
F N>N N F H N 33 N 33
(S)-6-Methyl-N5-(3,4,5-trifluorophenyl)-N 3-((R)-1,1,1-trifluoropropan-2-yl )-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide33 F 0OH F 0N0 Nn H ~. N_. 0 34 34
(S)-N5-(3,4-Difluorophenyl)-6-methyl-N 3-((S)-tetrahydrofuran-3-yl)-6,7-di hydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide34 F
F N N N N6 H N N
35
Nl-(3-Methyltetrahydrofuran-3-yl)-N 7-(3,4,5-trifluorophenyl)-5,6-dihydroi midazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide35
F NN 0 N F
36 36
(R)-N2-(3,4-Difluorophenyl)-N 8 -(,1,1-trifluoropropan-2-yl)-3,4-dihydrop yrrolo[1,2-a]pyrazine-2,8(1IH)-dicarboxamide36
F N N F H N/N 37 37
(R)-N7-(2-(Difluoromethyl)pyridin-4-yl)-N 1 -(,1,1-trifluoropropan-2-yl)-5, 6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 37 F 0 H
F N N 1 0N F 38 HN, 38
(S)-N3 ,N5-Bis(3,4-difluorophenyl)-6-methyl-6,7-dihydropyrazolo[1,5-a]py razine-3,5(4H)-dicarboxamide 38
F N N F H - N 39 39 (S)-N5-(3,4-Difluorophenyl)-6-methyl-N 3-((R)-1,1,1-trifluoropropan-2-yl) 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 39 F F F 0 0 NH F N N N H .. N
40
(S)-N-(4-Fluoro-3-methylphenyl)-6-methyl-N 3 -((R)-1,1,1-trifluoropropan 2-yl)-6,7-dihydro-[ 1,2,3]triazolo[ 1,5-a]pyrazine-3,5(4H)-dicarboxamide 40 F O H F
F N N F H N 41 41
(S)-N7-(3,4-Difluorophenyl)-6-methyl-N-((S)-1,1,1-trifluoropropan-2-yl) 5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 41
F N N H N, N
42 42
(R)-N5-(3,4-Difluorophenyl)-7-methyl-N 3-((R)-1,1,1-trifluoropropan-2-yl) 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 42
F 0 H F
F N N H NN 43 43
(S)-N5-(3,4-Difluorophenyl)-6-methyl-N 3-((S)-1,1,1-trifluoropropan-2-yl) 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 43 F 0H F 0N F N N N H NN
44 44
(R)-N5-(3-Cyano-4-fluorophenyl)-7-methyl-N 3-((R)-1,1,1-trifluoropropan 2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 44 F F O H F
N F N lN N' H , , 'N
45 (S)-N5-(3-Cyano-4-fluorophenyl)-6-methyl-N 3-((R)-1,1,1-trifluoropropan 2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 45
0 NH
N N NH N H ,- N,//N 46
46
(S)-N7-(3-Cyano-4-fluorophenyl)-6-methyl-N 1 -(1-methylcyclobutyl)-5,6-d ihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 46 F. 0 H F
N N F N H N N
47 47
(R)-N7 -(3-Cyano-4-fluorophenyl)-5-methyl-N 1 -((R)-1,1,1-trifluoropropan 2-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 47
F o7
48 N N N N H -- N _ /N
48
(S)-N7 -(3-Cyano-4-fluorophenyl)-6-methyl-N-(1-methylcyclopropyl)-5,6 dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 48
~H3F F N N H C
49 H3 C N
49
(R)-N5-(3,4-Difluorophenyl)-6-methyl-N 3-((R)-1,1,1-trifluoropropan-2-yl) 6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide49 F 0 H 0 N NC N N H " N . N
50
(S)-N-(Tert-butyl)-N 7-(3-cyano-4-fluorophenyl)-6-methyl-5,6-dihydroimi dazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide50 F. 0 H 0 N NC N N F H , NON 51 51
(S)-N7 -(3-Cyano-4-fluorophenyl)-N 1 -((R)-1-fluoropropan-2-yl)-6-methyl-5 ,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 51 F 0 H F
N N " F H N 52 52
(S)-N7 -(3-Cyano-4-fluorophenyl)-6-methyl-N 1 -((S)-1,1,1-trifluoropropan-2 -yl)-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 52 F N N F
H NON
53 53
(R)-N7-(3,4-Difluorophenyl)-6-methyl-N 1 -((R)-1,1,1-trifluoropropan-2-yl) 5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide53 F 0 H F
NC N N C'F HC N 3C H3C 54 54
(R)-N7 -(3-Cyano-4-fluorophenyl)-6-methyl-N 1 -((R)-1,1,1-trifluoropropan 2-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide54
F 0 H F
N N I F N H N# N
55
(R)-N7-(3-Cyano-4-fluorophenyl)-6-methyl-N-((S)-1,1,1-trifluoropropan 2-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide55 F 0 H F N -N
56 56
(S)-N7-(3-Cyano-4-fluorophenyl)-5-methyl-N-((R)-1,1,1-trifluoropropan 2-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide56 F O H F
NC N N N F H N'
57 57
N5-(3-Cyano-4-fluorophenyl)-7-methyl-N 3 -((R)-1,1,1-trifluoropropan-2-yl )-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide57 F. 0 H F 0 NF H 3C N N'- jF H N-N 58 58
(S)-N7 -(4-Fluoro-3-methylphenyl)-6-methyl-N-((R)-1,1,1-trifluoropropan 2-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide58 or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides a compound of formula (IA):
0 ORa
A4) (RSH N N N /Y N" .
(R ),
(IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Ra is hydrogen or alkyl; ring A is aryl or heteroaryl; Y is N or CR5 ;
Q is N or CH; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6
, -C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; each R4 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6
, -C(O)OR 6 and -S(O)mR 6 ; R 5 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 6 is selected from the group consisting of hydrogen, alkyl, haloalkyl, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is 0, 1, 2 or 3; m is 0, 1 or 2; and s is 0, 1, 2, 3 or 4. In another aspect, the present invention provides a compound of formula (IC):
0 OH
(R4), N JN Z--- 'e -H(R 3 N- /
(IC) or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: ring A is aryl or heteroaryl; Y is N or CR; Q is N or CH; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 ,
-C(O)OR6 and -S(O)mR 6 , and preferably hydrogen or alkyl; each R4 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 ,
-C(O)OR6 and -S(O)mR 6 ; R 5 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 6 is selected from the group consisting of hydrogen, alkyl, haloalkyl, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is 0, 1, 2 or 3; m is 0, 1 or 2; and s is 0, 1, 2, 3 or 4. They are intermediates for preparing the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof. Typical compounds of formula (IA) include, but are not limited to: Example Structure and name of the compound No. F F N 0 H N.N Id 1d Methyl 7-((3,4,5-trifluorophenyl)carbamoyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyr azine-1-carboxylate 0
F) N NC H T N-N
2e 2e
Methyl 5-((3,4-difluorophenyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyraz ine-3-carboxylate F
F 0 0 F N N H N 4a 4a
Methyl 5-((3,4,5-trifluorophenyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr azine-3-carboxylate F. 0 \ F: N NN H N
5b 5b Ethyl 7-((3,4-difluorophenyl)carbamoyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazi ne-i-carboxylate
F 00
F N N H N
6f 6f Methyl (S)-7-((3,4-difluorophenyl)carbamoyl)-6-methyl-5,6,7,8-tetrahydroimidaz o[1,5-a]pyrazine-1-carboxylate6f
F N N
7eH 7e Methyl (S)-5-((3,4-difluorophenyl)carbamoyl)-6-methyl-4,5,6,7-tetrahydropyrazol o[1,5-a]pyrazine-3-carboxylate7e
0 OH F F N1 N 7f H ,,N'N
7f (S)-5-((3,4-Difluorophenyl)carbamoyl)-6-methyl-4,5,6,7-tetrahydropyrazo lo[1,5-a]pyrazine-3-carboxylic acid 7f F 0
Na H0 L. 0\ 9a 9a Methyl 5-((3-cyano-4-fluorophenyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a] pyrazine-3-carboxylate 9a 0 OH
9b N O NO 9b 5-((3-Cyano-4-fluorophenyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a] pyrazine-3-carboxylic acid 9b F F 0 0 0 F N NN H a H N'N 10a Methyl (S)-6-methyl-5-((3,4,5-trifluorophenyl)carbamoyl)-4,5,6,7-tetrahydropyra zolo[1,5-a]pyrazine-3-carboxylate10a
F F 0 OH
F N NkOH b H e N'N 10b (S)-6-Methyl-5-((3,4,5-trifluorophenyl)carbamoyl)-4,5,6,7-tetrahydropyra zolo[1,5-a]pyrazine-3-carboxylic acid 10b F 0 0 N N NO N/
1a 1a Methyl (S)-7-((3-cyano-4-fluorophenyl)carbamoyl)-6-methyl-5,6,7,8-tetrahydroi midazo[1,5-a]pyrazine-1-carboxylate lla F 0 OH
N H N N 11 1lb H,,,
11b (S)-7-((3-Cyano-4-fluorophenyl)carbamoyl)-6-methyl-5,6,7,8-tetrahydroi midazo[l,5-a]pyrazine-1-carboxylic acid 11b F F 0 0 -0 F3a& H NJN 13a 13a Methyl (S)-6-methyl-7-((3,4,5-trifluorophenyl)carbamoyl)-5,6,7,8-tetrahydroimid azo[1,5-a]pyrazine-1-carboxylate13a F F 00 H
F N N OH 13b H\ N
13b (S)-6-Methyl-7-((3,4,5-trifluorophenyl)carbamoyl)-5,6,7,8-tetrahydroimid azo[1,5-a]pyrazine-1-carboxylic acid 13b F F 0
F NN -OH
17e H N N 17e 5-((3,4,5-Trifluorophenyl)carbamoyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[l, 5-a]pyrazine-3-carboxylic acid 17e F F 0 N OOH 19a F N N O H N /
19a
5-((3,4,5-Trifluorophenyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[ 1,5-a]py razine-3-carboxylic acid 19a
F NNN F H 37c Ethyl 7-((2-(difluoromethyl)pyridin-4-yl)carbamoyl)-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyrazine-1-carboxylate 37c F 0 0 OH
H N 45d N N
45d (S)-5-((3-Cyano-4-fluorophenyl)carbamoyl)-6-methyl-4,5,6,7-tetrahydro-[ 1,2,3]triazolo[1,5-a]pyrazine-3-carboxylic acid 45d In another aspect, the present invention provides a compound of formula (IIIA): OH N
(M)t- HN 'R
(R 3) N (iIA) or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: M is trifluoroacetic acid or hydrochloric acid; R 1 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted by one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6 , -C(O)R 6, -C(O)OR 6 and -S(O)mR 6; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 ,
-C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; tisOor 1; and n is 0, 1, 2 or 3. It is an intermediate for preparing the compound of formula (III) or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof. Typical intermediate compounds include, but are not limited to: Example Structure and name of the compound
No. O H F F_0 N __'F OH-HN j F F N 3c
/ 3c
(R)-N-(1,1,1-Trifluoropropan-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazi ne-1-carboxamide trifluoroacetate
HN F N _N
(R)-N-(1,1,1-Trifluoropropan-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazi ne-i-carboxamide
OH HN F N'N 15c 15c
(S)-6-Methyl-N-((R)-1,1,1-trifluoropropan-2-yl)-4,5,6,7-tetrahydropyrazolo
[1,5-a]pyrazine-3-carboxamide trifluoroacetate 15c 0 H F
HN N F HN F
(S)-6-Methyl-N-((R)-1,1,1-trifluoropropan-2-yl)-4,5,6,7-tetrahydropyrazolo
[1,5-a]pyrazine-3-carboxamide In another aspect, the present invention provides a method for preparing the compound of formula (I) according to the present invention, comprising a step of: 0 R2~o
R1 (R4) N ON ( 1BHN \(R4)
( ) (R3)./--
(IA ) (I )
reacting a compound of formula (IA) with a compound of formula (IB) or a salt thereof to obtain the compound of formula (I), wherein: Ra is hydrogen or alkyl; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 ,
-C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and ring A, Y, Q, R1 , R 2 , R4 , s and n are as defined in formula (I).
In another aspect, the present invention provides a method for preparing the compound of formula (I) according to the present invention, comprising a step of: 2 2~R 4 OH HN( 0 N
A N1 N -_-Z (IB)\R1 A N ), N -_'R1
(R3), '-N* (R3) n
(IC) (I)
reacting a compound of formula (IC) with a compound of formula (IB) or a salt thereof to obtain the compound of formula (I), wherein: each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6
, -C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and ring A, Y, Q, R1 , R 2 , R4 , s and n are as defined in formula (I). In another aspect, the present invention provides a method for preparing the compound of formula (II) according to the present invention, comprising a step of: 0 O~0H 0O~0 N 1 A 'N R1 A4) aNN H 2N-R H N ~ (11B) (R) H N,/Y (R% 3) n__-"__Q 3 (R ).
(IA ) (II)
reacting a compound of formula (IA) with a compound of formula (JIB) or a salt thereof to obtain the compound of formula (II), wherein: Ra is hydrogen or alkyl; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 ,
-C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and ring A, Y, Q, R1 , R4 , s and n are as defined in formula (II). In another aspect, the present invention provides a method for preparing the compound of formula (II) according to the present invention, comprising a step of: O H O 0 N 1 AR4)OH H 2N-R 4 A NN R1 SH K/N&_(IB HR) (R )n
(IC) reacting a compound of formula (IC) with a compound of formula (JIB) or a salt thereof to obtain the compound of formula (II), wherein: each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6
, -C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and ring A, Y, Q, R1 , R4 , s and n are as defined in formula (II). In another aspect, the present invention provides a method for preparing the compound of formula (III), formula (IV), formula (V) or formula (VI) according to the present invention, comprising a step of: 0 OH
R4) A N N OZ a H 2N-R 1 A N NR1 H NR) J (IIB) ()H L$NdN (R ) (R(R N3
(111l-a ) (11ll) reacting a compound of formula (III-a) with a compound of formula (IIB) or a salt thereof to obtain the compound of formula (III), or
0 0 N N R1 N LN H N-R 1 A4) N (R4) SH(R)?~ IB 2 (R) seH 'T7~N (R3 .
(IV-a) (IV) reacting a compound of formula (IV-a) with a compound of formula (IIB) or a salt thereof to obtain the compound of formula (IV), 0 O~0H
4) H N H 2N-R 1 A HRNN ) R1 (R3/ 3)~4 -N') (R 3 )~ (R3 )
(V-a) (V) reacting a compound of formula (V-a) with a compound of formula (IIB) or a salt thereof to obtain the compound of formula (V), or
ORa HN O 0O~0 N 1 R4)N / (II N H2N-R 4 N N R1
(R(R 3
) (VI-a) (VI) reacting a compound of formula (VI-a) with a compound of formula (JIB) or a salt thereof to obtain the compound of formula (VI), wherein: Ra is hydrogen or alkyl; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6
, -C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and ring A, R 1 , R 4 , s and n are as defined in formula (I). In another aspect, the present invention provides a method for preparing the compound of formula (III), comprising a step of: 0 H 0OH 0 N N 'R1 A"R1 (M)t- HN NR 4 (R ) A NH 2 (R 4 ) A N N N
3 (R 3 )" Bis(trichloromethyl)carbonate (R )n
reacting a compound of formula (IIIA) or a salt thereof with a compound of formula (IIB') or a salt thereof and bis(trichloromethyl)carbonate to obtain the compound of formula (III), wherein: each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 ,
-C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and M is trifluoroacetic acid or hydrochloric acid; t is 0 or 1; ring A, R 1 , R 4 , s and n are as defined in formula (III). In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier(s), diluent(s) or excipient(s). The present invention also relates to a method for preparing the above composition, comprising a step of mixing the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof with the pharmaceutically acceptable carrier(s), diluent(s) or excipient(s). The present invention further relates to a use of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same in the preparation of a capsid protein inhibitor. The present invention further relates to a use of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same in the preparation of a medicament for preventing and/or treating a viral infection disease. The virus can be hepatitis B virus, influenza virus, herpes virus and AIDS virus, and the diseases can be hepatitis B, influenza, herpes and AIDS. The present invention further relates to the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament. The medicament is preferably a medicament for preventing and/or treating a viral infection disease. The virus can be hepatitis B virus, influenza virus, herpes virus and AIDS virus, and the diseases can be hepatitis B, influenza, herpes and AIDS. The present invention also relates to the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same, for use as a capsid protein inhibitor. The present invention also relates to a method for preventing and/or treating a viral infection disease, comprising a step of administrating to a patient in need thereof a therapeutically effective dose of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same as a capsid protein inhibitor. The virus can be hepatitis B virus, influenza virus, herpes virus and AIDS virus, and the diseases can be hepatitis B, influenza, herpes and AIDS. The pharmaceutical composition containing the active ingredient can be in a form suitable for oral administration, for example, a tablet, troche, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, syrup or elixir. An oral composition can be prepared according to any known method in the art for the preparation of pharmaceutical composition. Such a composition can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants and preservatives, in order to provide a pleasing and palatable pharmaceutical formulation. The tablet contains the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. The tablet can be uncoated or coated by means of a known technique to mask drug taste or delay the disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby providing sustained release over a long period of time.
An oral formulation can also be provided as soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or the active ingredient is mixed with a water-soluble carrier or an oil medium. An aqueous suspension contains the active ingredient in admixture with excipients suitable for the manufacture of an aqueous suspension. Such excipients are suspending agents, dispersants or wetting agents. The aqueous suspension can also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweeteners. An oil suspension can be formulated by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension can contain a thickener. The aforementioned sweeteners and flavoring agents can be added to provide a palatable formulation. These compositions can be preserved by adding an antioxidant. The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, or a mineral oil, or a mixture thereof. Suitable emulsifying agents can be naturally occurring phospholipids. The emulsion can also contain a sweetening agent, flavoring agent, preservative and antioxidant. Such a formulation can also contain a demulcent, preservative, colorant and antioxidant. The pharmaceutical composition of the present invention can be in the form of a sterile injectable aqueous solution. Acceptable vehicles or solvents that can be used are water, Ringer's solution or isotonic sodium chloride solution. The sterile injectable formulation can be a sterile injectable oil-in-water micro-emulsion in which the active ingredient is dissolved in the oil phase. The injectable solution or micro-emulsion can be introduced into a patient's bloodstream by local bolus injection. Alternatively, the solution and micro-emulsion are preferably administrated in a manner that maintains a constant circulating concentration of the compound of the present invention. In order to maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is Deltec CADD-PLUS. TM. 5400 intravenous injection pump. The pharmaceutical composition of the present invention can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. Such a suspension can be formulated with suitable dispersants or wetting agents and suspending agents as described above according to known techniques. The sterile injectable formulation can also be a sterile injectable solution or suspension prepared in a nontoxic parenterally acceptable diluent or solvent. Moreover, sterile fixed oils can easily be used as a solvent or suspending medium. For this purpose, any blended fixed oil can be used. In addition, fatty acids can also be used to prepare injections. The compound of the present invention can be administrated in the form of a suppository for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures, but liquid in the rectum, thereby melting in the rectum to release the drug. It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors including but not limited to, the following factors: activity of a specific compound, age of the patient, weight of the patient, general health of the patient, behavior of the patient, diet of the patient, administration time, administration route, excretion rate, drug combination and the like. In addition, the optimal treatment, such as treatment mode, daily dose of the compound of the present invention or the type of pharmaceutically acceptable salt thereof can be verified by traditional therapeutic regimens.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise stated, the terms used in the specification and claims have the meanings described below. The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group comprising 1 to 20 carbon atoms, preferably an alkyl having 1 to 12 carbon atoms, and more preferably an alkyl having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferably, the alkyl group is a lower alkyl having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,2,2-dimethylbutyl,1,3-dimethylbutyl,2-ethylbutyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. The alkyl group can be substituted or unsubstituted. When substituted, the substituent group(s) can be substituted at any available connection point. The substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, alkoxycarbonyl, -OR 6, -C(O)R 6 , -C(O)OR 6 and -S(O)mR 6 . The term "alkoxy" refers to an -O-(alkyl) or an -O-(unsubstitutedcycloalkyl) group, wherein the alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. The alkoxy can be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, alkoxycarbonyl, -OR6 , -C(O)R6 , -C(O)OR6 and -S(O)mR6
. The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like. Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring. The term "spiro cycloalkyl" refers to a 5 to 20 membered polycyclic group with individual rings connected through one shared carbon atom (called a spiro atom), wherein the rings can contain one or more double bonds, but none of the rings has a completely conjugated n-electron system. The spiro cycloalkyl is preferably 6 to 14 membered spiro cycloalkyl, and more preferably 7 to 10 membered spiro cycloalkyl. According to the number of the spiro atoms shared between the rings, the spiro cycloalkyl can be divided into mono-spiro cycloalkyl, di-spiro cycloalkyl, or poly-spiro cycloalkyl, and the spiro cycloalkyl is preferably a mono-spiro cycloalkyl or di-spiro cycloalkyl, and more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro cycloalkyl. Non-limiting examples of spiro cycloalkyl include:
and
The term "fused cycloalkyl" refers to a 5 to 20 membered all-carbon polycyclic group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated -electron system. The fused cycloalkyl is preferably 6 to 14 membered fused cycloalkyl, and more preferably 7 to 10 membered fused cycloalkyl. According to the number of membered rings, the fused cycloalkyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and the fused cycloalkyl is preferably bicyclic or tricyclic fused cycloalkyl, and more preferably 5-membered/5-membered, or 5-membered/6-membered bicyclic fused cycloalkyl. Non-limiting examples of fused cycloalkyl include: and
The term "bridged cycloalkyl" refers to a 5 to 20 membered all-carbon polycyclic group, wherein every two rings in the system share two disconnected carbon atoms, wherein the rings can have one or more double bonds, but none of the rings has a completely conjugated n-electron system. The bridged cycloalkyl is preferably 6 to 14 membered bridged cycloalkyl, and more preferably 7 to 10 membered bridged cycloalkyl. According to the number of membered rings, the bridged cycloalkyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and the bridged cycloalkyl is preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl, and more preferably bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyl include:
and .
The cycloalkyl ring can be fused to the ring of aryl, heteroaryl or heterocyclyl, wherein the ring bound to the parent structure is cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl and the like. The cycloalkyl can be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, alkoxycarbonyl, -OR 6 , -C(O)R6 ,
-C(O)OR6 and -S(O)mR6 .
The term "heterocyclyl" refers to a 3 to 20 membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from the group consisting of N, 0 and S(O)m (wherein m is an integer of 0 to 2), but excluding -0-0-, -O-S- or -S-S- in the ring, with the remaining ring atoms being carbon atoms. Preferably, the heterocyclyl has 3 to 12 ring atoms wherein 1 to 4 atoms are heteroatoms; more preferably, 3 to 8 ring atoms wherein 1 to 3 atoms are heteroatoms; and most preferably 3 to 6 ring atoms wherein 1 to 2 atoms are heteroatoms. Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like, and preferably piperidinyl, piperazinyl or morpholinyl. Polycyclic heterocyclyl includes a heterocyclyl having a spiro ring, fused ring or bridged ring. The term "spiro heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclyl group with individual rings connected through one shared atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from the group consisting of N, 0 and S(O)m (wherein m is an integer of 0 to 2), with the remaining ring atoms being carbon atoms, where the rings can contain one or more double bonds, but none of the rings has a completely conjugated n-electron system. The spiro heterocyclyl is preferably 6 to 14 membered spiro heterocyclyl, and more preferably 7 to 10 membered spiro heterocyclyl. According to the number of the spiro atoms shared between the rings, the spiro heterocyclyl can be divided into mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiro heterocyclyl, and the spiro heterocyclyl is preferably mono-spiro heterocyclyl or di-spiro heterocyclyl, and more preferably 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro heterocyclyl. Non-limiting examples of spiro heterocyclyl include:
Ng N
0N S and
The term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of atoms with another ring, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated n-electron system, and wherein one or more ring atoms are heteroatoms selected from the group consisting of N, 0 and S(O)m (wherein m is an integer of 0 to 2), with the remaining ring atoms being carbon atoms. The fused heterocyclyl is preferably 6 to 14 membered fused heterocyclyl, and more preferably 7 to 10 membered fused heterocyclyl. According to the number of membered rings, the fused heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, and the fused heterocyclyl is preferably bicyclic or tricyclic fused heterocyclyl, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclylinclude:
H 0 N
H H H
_ N' O N and 0 The term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclyl group, wherein every two rings in the system share two disconnected atoms, wherein the rings can have one or more double bonds, but none of the rings has a completely conjugated n-electron system, and wherein one or more ring atoms are heteroatoms selected from the group consisting of N, 0 and S(O)m (wherein m is an integer of 0 to 2), with the remaining ring atoms being carbon atoms. The bridged heterocyclyl is preferably 6 to 14 membered bridged heterocyclyl, and more preferably 7 to 10 membered bridged heterocyclyl. According to the number of membered rings, the bridged heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and the bridged heterocyclyl is preferably bicyclic, tricyclic or tetracyclic bridged heterocyclyl, and more preferably bicyclic or tricyclic bridged heterocyclyl. Non-limiting examples of bridged heterocyclyl include:
NN
N and
The heterocyclyl ring can be fused to the ring of aryl, heteroaryl or cycloalkyl, wherein the ring bound to the parent structure is heterocyclyl. Non-limiting examples thereof include:
H H H N ~ N N NH and the like. The heterocyclyl can be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, alkoxycarbonyl,
-OR 6, -C(O)R 6, -C(O)OR6 and -S(O)mR6
. The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic ring or polycyclic fused ring (i.e. each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) having a conjugated -electron system, preferably 6 to 10 membered aryl, for example, phenyl and naphthyl. The aryl is more preferably phenyl. The aryl ring can be fused to the ring of heteroaryl, heterocyclyl or cycloalkyl, wherein the ring bound to the parent structure is aryl ring. Non-limiting examples thereof include:
-~ NK'H H N O
H H H N N~ N N N N lz N <\ N
/ N 0 and The aryl can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl. The term "heteroaryl" refers to a 5 to 14 membered heteroaromatic system having 1 to 4 heteroatoms selected from the group consisting of 0, S and N. The heteroaryl is preferably 5 to 10 membered heteroaryl having 1 to 3 heteroatoms, more preferably 5 or 6 membered heteroaryl having 1 to 2 heteroatoms; preferably for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl and the like, preferably imidazolyl, tetrazolyl, pyridyl, thienyl, pyrazolyl, pyrimidinyl, thiazolyl, and more preferably pyridyl. The heteroaryl ring can be fused to the ring of aryl, heterocyclyl or cycloalkyl, wherein the ring bound to the parent structure is heteroaryl ring. Non-limiting examples thereof include:
0 NH -~ / N I N N N N N N 0:C N HN - HN N HN- HN an N N. ~ N K-N/ and AS
The heteroaryl can be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, alkoxycarbonyl, -OR6 ,
-C(O)R 6, -C(O)OR6 and -S(O)mR6 .
The term "amino protecting group" refers to a group which prevents an amino group from reaction when other parts of the molecular are subject to a reaction, and can be easily removed. Non-limiting examples include tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl and the like. These groups can be optionally substituted by one to three substituents selected from the group consisting of halogen, alkoxy and nitro. The amino protecting group is preferably p-methoxybenzyl. The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein the alkyl is as defined above. The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, wherein the alkoxy is as defined above. The term "hydroxyalkyl" refers to an alkyl group substituted by hydroxy(s), wherein the alkyl is as defined above. The term "hydroxy" refers to an -OH group. The term "halogen" refers to fluorine, chlorine, bromine or iodine. The term "amino" refers to a -NH 2 group. The term "cyano" refers to a -CN group. The term "nitro" refers to a -NO 2 group. The term "oxo" refers to a =0 group. The term "carbonyl" refers to a C=O group. The term "carboxy" refers to a -C(O)OH group. The term "alkoxycarbonyl" refers to a -C(O)O(alkyl) or -C(O)O(cycloalkyl) group, wherein the alkyl and cycloalkyl are as defined above. The term "acyl halide" refers to a compound containing a -C(O)-halogen group. "Optional" or "optionally" means that the event or circumstance described subsequently can, but need not, occur, and such a description includes the situation in which the event or circumstance does or does not occur. For example, "the heterocyclyl optionally substituted by an alkyl" means that an alkyl group can be, but need not be, present, and such a description includes the situation of the heterocyclyl being substituted by an alkyl and the heterocyclyl being not substituted by an alkyl. "Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, and more preferably 1 to 3 hydrogen atoms, independently substituted by a corresponding number of substituents. It goes without saying that the substituents only exist in their possible chemical position. The person skilled in the art is able to determine whether the substitution is possible or impossible by experiments or theory without paying excessive efforts. For example, the combination of amino or hydroxy having free hydrogen and carbon atoms having unsaturated bonds (such as olefinic) may be unstable. A "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein or physiologically/pharmaceutically acceptable salts or prodrugs thereof with other chemical components, and other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient so as to show biological activity. A "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is safe and effective in mammals and has the desired biological activity. R 6 and m are as defined in formula (I).
Synthesis Method of the Compound of the Present Invention In order to achieve the object of the present invention, the present invention applies the following technical solutions: Scheme I A method for preparing the compound of formula (I) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following steps of: x 0 x
sRHN 4- (R) N- ( )NH 2 (R3 N'Q Bis(trichloromethyl)carbonate 3 IB-) (1-2) Step1 (1-3) Step2
0 0 R l 0(- )
A N 'N HN1 0RN H N QN~ ( IBH A(R4)s N N 3 N-&/ (R )n Step 3 Q 3 (R )
(IA )
in Step 1, a compound of formula (IIB') is reacted with a compound of formula (1-2) and bis(trichloromethyl)carbonate under an alkaline condition to obtain a compound of formula (1-3); in Step 2, the compound of formula (1-3) is reacted with carbon monoxide in the presence of a catalyst under an alkaline condition to obtain a compound of formula (IA); in Step 3, the compound of formula (IA) is reacted with a compound of formula (IB) or a salt thereof to obtain the compound of formula (I). The reagent that provides an alkaline condition includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate. The catalyst includes, but is not limited to, Pd/C, Raney Ni, platinum dioxide, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl,
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, 1,1'-bis(dibenzylphosphoryl)ferrocene palladium dichloride, tris(dibenzylideneacetone)dipalladium and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and preferably
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl. The condensing agent includes, but is not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-NN,NVN-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N,NN t-tetramethyluronium hexafluorophosphate, 0-(7-azabenzotriazol-1-yl)-NN,NN t -tetramethyluronium hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,NN'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphoniumhexafluorophosphate, and preferably 2-(7-oxobenzotriazole)-N,N,NN-tetramethyluroniumhexafluorophosphate. The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof. Wherein: Ra is hydrogen or alkyl, and preferably hydrogen, methyl or ethyl; X is halogen, and preferably bromine; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 ,
-C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and ring A, Y, Q, R1 , R 2 , R4 , s and n are as defined in formula (I).
Scheme II A method for preparing the compound of formula (I) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following steps of:
0 ORa 0 ORa
A (MH)tH (R 4)s N NON (R4)s NH 2 + N Bis(trichloromethyl)carbonate HN (R3)n(R 3 ), (IIB') (1-4) Step I ( IA) R2 0 OH HN 0 N
(R 4) ; A N> N -- Z ( \B Ai -NN ~ R1 4 H N OH IBHN (R )s H Step 2 (R )n Step 3 (R 3)n ( IC) (I)
in Step 1, a compound of formula (IIB') is reacted with a compound of formula (1-4) and bis(trichloromethyl)carbonate under an alkaline condition to obtain a compound of formula (IA); in Step 2, the compound of formula (IA) is subjected to a hydrolysis reaction under an alkaline condition to obtain a compound of formula (IC); in Step 3, the compound of formula (IC) and a compound of formula (IB) or a salt thereof are subjected to a condensation reaction to obtain the compound of formula (I). The reagent that provides an alkaline condition includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate. The condensing agent includes, but is not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N-dicyclohexylcarbodiimide, N,N-diisopropylcarbodiimide, 0-benzotriazole-N,N,NN-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N,NN-tetramethyluronium hexafluorophosphate, 0-(7-azabenzotriazol-1-yl)-N,N,NN-tetramethyluronium hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphoniumhexafluorophosphate, and preferably 2-(7-oxobenzotriazole)-N,N,N,N-tetramethyluroniumhexafluorophosphate. The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof. Wherein: Ra is alkyl, and preferably methyl or ethyl; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6
, -C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and ring A, Y, Q, R1 , R 2 , R4 , s and n are as defined in formula (I).
Scheme III A method for preparing the compound of formula (II) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following step of: 0 0 OR~a 0 H 4) NN S _ (11B) A N"A, Oa ( H 2 N-R 0 N R1 H / YN IN (R 4) NN (R3). N (R3)n (IA) (ii) Reacting a compound of formula (IA) with a compound of formula (JIB) or a salt thereof under an alkaline condition to obtain the compound of formula (II). The reagent that provides an alkaline condition includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate. The condensing agent includes, but is not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N-dicyclohexylcarbodiimide, N,N-diisopropylcarbodiimide, 0-benzotriazole-N,N,NN-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N,NN-tetramethyluronium hexafluorophosphate, 0-(7-azabenzotriazol-1-yl)-N,N,NN-tetramethyluronium hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphoniumhexafluorophosphate, and preferably 2-(7-oxobenzotriazole)-N,N,N,N-tetramethyluroniumhexafluorophosphate. The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof. Wherein:
Ra is hydrogen or alkyl, and preferably hydrogen, methyl or ethyl; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6
, -C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and ring A, Q, Y, R1 , R4 , s and n are as defined in formula (II).
Scheme IV A method for preparing the compound of formula (II) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following step of: 0 H 0 0H N IR 1 N(N OH H2 N-R RR A SH(4LK N// IIB) HN N," 3 (Q (R (R)n
(IC)
Reacting a compound of formula (IC) with a compound of formula (JIB) or a salt thereof under an alkaline condition to obtain the compound of formula (II). The reagent that provides an alkaline condition includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate. The condensing agent includes, but is not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-NN,NVN-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N,NN t-tetramethyluronium hexafluorophosphate, 0-(7-azabenzotriazol-1-yl)-NN,NN t -tetramethyluronium hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,NN'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphoniumhexafluorophosphate, and preferably 2-(7-oxobenzotriazole)-N,N,NN-tetramethyluroniumhexafluorophosphate. The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof.
Wherein: each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6
, -C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and ring A, Q, Y, R1 , R4 , s and n are as defined in formula (II).
Scheme V A method for preparing the compound of formula (III) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following steps of: 0ORa 0 OR a HN OA()N N N A+N (R) 5 HN (Rk)s NH 2 + 3 )/ N -- / Bis(trichloromethyl)carbonate N
/ Step1 (R) Step 2 11')( n (11-1 (Ill-a
) 0 OH 0 H 1 A4)s N N H 2N-R 0 NNR
)n R 3 ' N ~Step 3 s (R3 N ( 111-b)
in Step 1, a compound of formula (IB') is reacted with a compound of formula (111-1) and bis(trichloromethyl)carbonate under an alkaline condition to obtain a compound of formula (III-a); in Step 2, the compound of formula (III-a) is subjected to a hydrolysis reaction under an alkaline condition to obtain a compound of formula (III-b); in Step 3, the compound of formula (III-b) is reacted with a compound of formula (IB) or a salt thereof to obtain the compound of formula (III). The reagent that provides an alkaline condition includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate. The condensing agent includes, but is not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-NN,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole,
O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, 0-(7-azabenzotriazol-1-yl)-NN,N,N'-tetramethyluronium hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N,N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate, and preferably 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate. The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof. Wherein: Ra is alkyl, and preferably methyl or ethyl; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6
, -C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and ring A, R 1 , R 4 , s and n are as defined in formula (III).
Scheme VI A method for preparing the compound of formula (IV) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following steps of: 0ORa 0 0Ra N HN (R4) N
(R4) NH2 +(R3 N N Bis(trichloromethyl)carbonate (R3 N'N Step 1 Step 2 (11') (IV-1 ) ( IV-a )
0 0H H A N 1 N OH 1 0 NN (R HH p-3R1) (R 4 ) A N (R3 5_ Step3R3y N N ( IV-b) (IV)
in Step 1, a compound of formula (IIB') is reacted with a compound of formula (IV-1) and bis(trichloromethyl)carbonate under an alkaline condition to obtain a compound of formula (IV-a); in Step 2, the compound of formula (IV-a) is subjected to a hydrolysis reaction under an alkaline condition to obtain a compound of formula (IV-b); in Step 3, the compound of formula (IV-b) is reacted with a compound of formula (IIB) or a salt thereof to obtain the compound of formula (IV). The reagent that provides an alkaline condition includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate. The catalyst includes, but is not limited to, Pd/C, Raney Ni, platinum dioxide, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl,
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, 1,1'-bis(dibenzylphosphoryl)ferrocene palladium dichloride, tris(dibenzylideneacetone)dipalladium and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and preferably
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl. The condensing agent includes, but is not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-N,N,NVN-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N,NN t-tetramethyluronium hexafluorophosphate, 0-(7-azabenzotriazol-1-yl)-NN,NN t -tetramethyluronium hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,NN'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphoniumhexafluorophosphate, and preferably 2-(7-oxobenzotriazole)-N,N,NN-tetramethyluroniumhexafluorophosphate. The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof. Wherein: Ra is alkyl, and preferably methyl or ethyl; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 ,
-C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and ring A, R 1 , R 4 , s and n are as defined in formula (I).
Scheme VII A method for preparing the compound of formula (III) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following steps of: O0H O H
R'N ORa H 2N-R 1 R1
N N (1B)N N/N 3 N/N (R3)( Step 1 3 k(R Step 2 (|||-4 ) (lllA
) (|||-3 )
0 H 0 N
4NH Bis(trichloromethyl)carbonate (R4 ), N N R1 + 2 Step 3 (R3)n
in Step 1, a compound of formula (111-3) is reacted with a compound of formula (IB) or a salt thereof in the presence of a condensing agent under an alkaline condition to obtain a compound of formula (111-4); in Step 2, the compound of formula (111-4) is subjected to a deprotection reaction under an acidic condition to obtain a compound of formula (IIIA) or a salt thereof; in Step 3, the compound of formula (1IIA) or a salt thereof is reacted with a compound of formula (IIB') or a salt thereof and bis(trichloromethyl)carbonate to obtain the compound of formula (III). The reagent that provides an alkaline condition includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate. The reagent that provides an acidic condition includes, but is not limited to, hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me 3SiCl and TMSOTf. The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof. Wherein: M is trifluoroacetic acid or hydrochloric acid; Ra is hydrogen or alkyl, and preferably hydrogen, methyl or ethyl; Rb is an amino protecting group, and preferably tert-butoxycarbonyl; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6
, -C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and t is 0 or 1; ring A, R, R 4 , s and n are as defined in formula (III).
Scheme VIII A method for preparing the compound of formula (V) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following steps of: 0 0
0 0 0 0 OH
4 + (R4), N HR) N (R4), N N OH R) N A~N -N N N 4 N 3 3 11 (R ) Step 1 (R ) Step2(R
(IIB') (V-1) (V-2) (V-3)
00 H 00 H NR4N Ar OH 2N0I "I (H H 4) 4 4 OH H'QN-RB (R ), R 3 Step 3 Step 4 (R Step 5 (R3 n (V-4 ) (V-a ) (y in Step 1, a compound of formula (IIB') is reacted with a compound of formula (V-1) under an alkaline condition to obtain a compound of formula (V-2); in Step 2, the compound of formula (V-2) is subjected to a reduction reaction in the presence of a reducing agent to obtain a compound of formula (V-3); in Step 3, the compound of formula (V-3) and an oxidizing agent are subjected to an oxidation reaction to obtain a compound of formula (V-4); in Step 4, the compound of formula (V-4) is subjected to an oxidation reaction in the presence of an oxidizing agent to obtain a compound of formula (V-a); in Step 5, the compound of formula (V-a) and a compound of formula (IB) or a salt thereof are subjected to a condensation reaction to obtain the compound of formula (V). The reagent that provides an alkaline condition includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate. The reducing agent includes, but is not limited to, lithium aluminum hydride, NaBH 4 , NaBH 4 -ZnCl2 and diisobutylaluminum hydride (DIBAL-H). The oxidizing agent includes, but is not limited to, pyridinium chlorochromate (PCC), Jones reagent, Collins reagent, pyridinium dichromate (PDC), oxalyl chloride (Swern oxidation), carbodiimide, sodium chlorite and potassium permanganate. The condensing agent includes, but is not limited to,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-N,N,NVN-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-NN,NN-tetramethyluronium hexafluorophosphate, 0-(7-azabenzotriazol-1-yl)-NN,NN t -tetramethyluronium hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,NVV-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate, and preferably 2-(7-oxobenzotriazole)-NN,NVV-tetramethyluronium hexafluorophosphate. The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof. Wherein: each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6
, -C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and ring A, R 1 , R 4 , s and n are as defined in formula (V).
Scheme IX A method for preparing the compound of formula (VI) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following steps of:
ORa 0 OR HN _ D.4) A N)N N 4) (RR S A:-LN/ NH 2 (R) se H LQ (R3)/ Bis(trichloromethyl)carbonate (R3) N Step 1 IIB' )( VI-1 )tp (VI-a)
O H H2N-R 1 0N N N R1 4 4 ) so H N Step 2 (R 3 )n
( VI)
in Step 1, a compound of formula (IIB') is reacted with a compound of formula (VI-1) and bis(trichloromethyl)carbonate under an alkaline condition to obtain a compound of formula (VI-2); in Step 2, the compound of formula (VI-a) is reacted with a compound of formula (IIB) or a salt thereof to obtain the compound of formula (VI).
The reagent that provides an alkaline condition includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate. The condensing agent includes, but is not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-N,N,NVN-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N,NN t-tetramethyluronium hexafluorophosphate, 0-(7-azabenzotriazol-1-yl)-NN,NN t -tetramethyluronium hexafluorophosphate, 2-(7-oxobenzotriazole)-NN,NN'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphoniumhexafluorophosphate, and preferably 2-(7-oxobenzotriazole)-N,N,NN-tetramethyluroniumhexafluorophosphate. The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof. Wherein: Ra is hydrogen or alkyl, and preferably hydrogen, methyl or ethyl; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 ,
-C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and ring A, R 1 , R 4 , s and n are as defined in formula (I).
Scheme X A method for preparing the compound of formula (VII) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following steps of:
0Oa0 0 a 0 -Z OR~ GR (R4)s HN R N G N NO 3 N Bis(trichloromethyl)carbonate (RH) H N/N )INH2 Step 1 (R3n Step 2
0 H
4 R1 1 (R )s N G ~ N~ 0 (11B)H OH H 2 N-R ( H(R3 HN/ M Step 3 (R3(n
(VII-b) (VIl)
in Step 1, a compound of formula (VII-1) is reacted with a compound of formula (III-1) and bis(trichloromethyl)carbonate under an alkaline condition to obtain a compound of formula (VII-a); in Step 2, the compound of formula (IV-a) is subjected to a hydrolysis reaction under an alkaline condition to obtain a compound of formula (VII-b); in Step 3, the compound of formula (VII-b) and a compound of formula (JIB) or a salt thereof are subjected to a condensation reaction to obtain the compound of formula (VII). The reagent that provides an alkaline condition includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate. The condensing includes, agent but is not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-NN,NVN-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N,NN t-tetramethyluronium hexafluorophosphate, 0-(7-azabenzotriazol-1-yl)-NN,NN t -tetramethyluronium hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,NN'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphoniumhexafluorophosphate, and preferably 2-(7-oxobenzotriazole)-N,N,NN-tetramethyluroniumhexafluorophosphate. The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof. Wherein:
Ra is alkyl, and preferably methyl or ethyl; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6
, -C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and R, R 4 , s and n are as defined in formula (I).
Scheme XI A method for preparing the compound of formula (VIII) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following steps of: 0 ORa ( ORa
4 (R%S$ HN -(R ) 0 -H 3 LrlN NH 2 + ( N' Bis(trichloromethyl)carbonate (R ) N
(IV-1) Step 1 (VIII-a) Step 2 (VII-1 )
0 H ( 0 ORa H2 N-R1 (R 4)s N 1 N R1 G N NANNIB 4 (R X' H K N Step3 (
(VIII-1) (V)ll
in Step 1, a compound of formula (VII-1) is reacted with a compound of formula (IV-1) and bis(trichloromethyl)carbonate under an alkaline condition to obtain a compound of formula (VIII-a); in Step 2, the compound of formula (VIII-a) is subjected to a hydrolysis reaction under an alkaline condition to obtain a compound of formula (VIII-b); in Step 3, the compound of formula (VIII-b) and a compound of formula (IIB) or a salt thereof are subjected to a condensation reaction to obtain the compound of formula (VIII). The reagent that provides an alkaline condition includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate. The condensing agent includes, but is not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole,
O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, 0-(7-azabenzotriazol-1-yl)-NN,N,N'-tetramethyluronium hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N,N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate, and preferably 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate. The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof. Wherein: Ra is alkyl, and preferably methyl or ethyl; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6
, -C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and R 1, R 4 , s and n are as defined in formula (I).
Scheme XII A method for preparing the compound of formula (VII-A) or formula (VIII-A) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following step of:
G" ORa (R 4 ) 0 H H N (R N4N NR H NNR9N)N RS + H2N _R8 H R 3 J, N N R8
( VII-a ) ( VII-B))VIA ( VII-A )
G' -OH R9 0X 4 N N + H 2N RS (R 4 N0 N R9 N' (VII-B) H R8
(VIII-a)
(VIII-A) reacting a compound of formula (VII-a) with a compound of formula (VII-B) or a salt thereof to obtain the compound of formula (VII-A); or reacting a compound of formula (VIII-a) with a compound of formula (VII-B) or a salt thereof to obtain the compound of formula (VIII-A). The reagent that provides an alkaline condition includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate. The condensing agent includes, but is not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-N,N,NVN-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N,NN t-tetramethyluronium hexafluorophosphate, 0-(7-azabenzotriazol-1-yl)-NN,NN t -tetramethyluronium hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,NVV-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphoniumhexafluorophosphate, and preferably 2-(7-oxobenzotriazole)-N,N,NVV-tetramethyluroniumhexafluorophosphate. The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof. Wherein: G is C or N; Ra is hydrogen or alkyl, and preferably hydrogen, methyl or ethyl; each R 3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 , -C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; R 8 is alkyl, preferably methyl; R 9 is alkyl, wherein the alkyl is optionally further substituted by one or more halogens; and R 4 and s are as defined in formula (I).
PREFERRED EMBODIMENTS
The present invention will be further described with reference to the following examples, but the examples should not be considered as limiting the scope of the present invention.
EXAMPLES The structures of the compounds were identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (6) are given in 10-6(ppm). NMR was determined by a Bruker AVANCE-400 machine. The solvents for determination were deuterated-dimethyl sulfoxide (DMSO-d 6 ), deuterated-chloroform (CDCl 3 ) and deuterated-methanol (CD 30D), and the internal standard was tetramethylsilane (TMS). MS was determined by a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, type: Finnigan LCQ advantage MAX). High performance liquid chromatography (HPLC) analysis was determined on an Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatographs. Chiral HPLC analysis was determined on an Agilent 1260 DAD high performance liquid chromatograph. High performance liquid preparation was carried out on Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs. Chiral preparation was carried out on a Shimadzu LC-20AP preparative chromatograph. CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO). Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate was used as the thin-layer silica gel chromatography (TLC) plate. The dimension of the silica gel plate used in TLC was 0.15 mm to 0.2 mm, and the dimension of the silica gel plate used in product purification was 0.4 mm to 0.5 mm. Yantai Huanghai 200 to 300 mesh silica gel was generally used as a carrier for silica gel column chromatography. The average kinase inhibition rates and IC5 0 values were determined by a NovoStar ELISA (BMG Co., Germany). The known starting materials of the present invention can be prepared by the known methods in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc., Dari chemical Company and the like. Unless otherwise stated, the reactions were carried out under argon atmosphere or nitrogen atmosphere. "Argon atmosphere" or "nitrogen atmosphere" means that a reaction flask is equipped with an argon or nitrogen balloon about1 L). "Hydrogen atmosphere" means that a reaction flask is equipped with a hydrogen balloon about1 L). Pressurized hydrogenation reactions were performed on a Parr 3916EKX hydrogenation instrument and a Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument. In hydrogenation reactions, the reaction system was generally vacuumed and filled with hydrogen, and the above operation was repeated three times. CEM Discover-S 908860 type microwave reactor was used in microwave reactions. Unless otherwise stated, the solution refers to an aqueous solution.
Unless otherwise stated, the reaction temperature is room temperature from 20°C to 30°C. The reaction process in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reactions, the eluent system in column chromatography and the developing solvent system in thin layer chromatography for purification of the compounds included: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, and C: petroleum ether/ethyl acetate system. The ratio of the volume of the solvent was adjusted according to the polarity of the compounds, and a small quantity of alkaline reagent such as triethylamine or acidic reagent such as acetic acid can also be added for adjustment.
Example 1 (R)-N7-(3,4,5-Trifluorophenyl)-N-(1,1,1-trifluoropropan-2-yl)-5,6-dihydroimidazo[1,5 a]pyrazine-1,7(8H)-dicarboxamide F F 0 H F
F N N N F H N F
F + HN Br F Br F NH HN N StepI F N N N Step2 F] NH 2 N N:: H N 1a 1b 1c
F F F. 0 0 F F. 0 0 HLF
F NN O HCIH 2 NF Step 3 F NN F H N H N
1d 1e 1 Step 1 1-Bromo-N-(3,4,5-trifluorophenyl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxam ide le 3,4,5-Trifluoroaniline la (0.365 g, 2.48 mmol, prepared according to the known method disclosed in "Tetrahedron Letters, 51(17), 2010, 2265-2268") and 1-bromo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine lb (501.36 mg, 2.48 mmol, Shanghai Shuya Pharmaceutical Technology Co., Ltd.) were dissolved in 30 mL of dichloromethane, followed by addition of triethylamine (753.26 mg, 7.44 mmol) and bis(trichloromethyl)carbonate (294.53 mg, 992.54 mol). After stirring for 12 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound le (300 mg, yield: 32.2%). MS m/z (ESI): 376.1 [M+1].
Step 2 Methyl 7-((3,4,5-trifluorophenyl)carbamoyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carbo xylate 1d Dicobalt octacarbonyl (525.03 mg, 1.54 mmol) and potassium carbonate (1.06 g, 7.68 mmol) were dissolved in 20 mL of methanol under a carbon monoxide atmosphere. The solution was stirred at 60°C for 15 minutes, followed by addition of compound le (300 mg, 767.71 mol) and methyl 2-chloroacetate (499.88 mg, 4.61 mmol). After stirring for 8 hours, the reaction solution was cooled to room temperature and filtrated. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 1d (70 mg, yield: 21.8%). MS m/z (ESI): 355.3 [M+1]. Step 3 (R)-N7-(3,4,5-Trifluorophenyl)-N-(1,1,1-trifluoropropan-2-yl)-5,6-dihydroimidazo[1,5 a]pyrazine-1,7(8H)-dicarboxamide Compound 1d (70 mg, 197.58 mol) and (2R)-1,1,1-trifluoropropan-2-amine hydrochloride le (59.09 mg, 395.16 mol, prepared according to the method disclosed in the patent application "CN102875270A") were dissolved in 10 mL of tetrahydrofuran, followed by dropwise addition of 0.988 [L of a IM solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran at 0°C. After completion of the addition, the reaction solution was warmed up slowly to room temperature, and stirred for 6 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was added with 15 mL of water, and extracted with ethyl acetate (15 mLx3). The organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 1 (15 mg, yield: 17.4%). MS m/z (ESI): 436.2 [M+1]. 1H NMR (400MHz, DMSO-d) 69.31 (s, 1H), 8.30 (d, 1H), 7.70 (s, 1H), 7.25-7.31 (m, 2H), 5.05 (s, 2H), 4.78-4.86 (m, 1H), 4.21-4.24 (m, 2H), 3.94-3.96 (m, 2H), 1.31-1.44 (dd, 3H).
Example 2 (R)-N5-(3,4-Difluorophenyl)-N 3-(1,1,1-trifluoropropan-2-yl)-6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-dicarboxamide F O H F F N - F
H
2
0 Br i0 0 0 0 0 0 F O11N- - >0NI - -------- 3 OH HN
+ O /N Step 1 Step 2 F HO NN NN F NN F NH NH'
2a 2b 2c 2d
FF 0 0 F 0N e N - N F Step 3 H N -- -- --.- Ste F N N F'
2e 2
Step 1 5-Tert-butyl 3-methyl 6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxylate 2b Dicobalt octacarbonyl (2.26 g, 6.62 mmol) and potassium carbonate (4.57 g, 33.09 mmol) were dissolved in 20 mL of methanol under a carbon monoxide atmosphere. The solution was stirred at 60°C for 15 minutes, followed by addition of tert-butyl 3-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate 2a (1 g, 3.31 mmol, prepared according to the known method disclosed in "ACS Medicinal Chemistry Letters, 2015, 6(1), 37-41") and methyl 2-chloroacetate (2.15 g, 19.86 mmol). After stirring for 16 hours, the reaction solution was concentrated under reduced pressure, added with 100 mL of ethyl acetate, filtrated, and washed with 100 mL of ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 2b (0.5 g, yield: 53%). MS m/z (ESI): 282.1 [M+1]. Step 2 Methyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate trifluoroacetate 2c Compound 2b (600 mg, 2.13 mmol) was dissolved in 10mL of dichloromethane, followed by addition of trifluoroacetic acid (2.43 g, 21.33 mmol). After completion of the addition, the reaction solution was stirred for 12 hours, and concentrated under reduced pressure to obtain the crude title compound 2c (250 mg), which was used directly in the next step without purification. MS m/z (ESI): 182.0 [M+1]. Step 3 Methyl 5-((3,4-difluorophenyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbox ylate 2e The crude compound 2c (200 mg, 1.10 mmol), 3,4-difluoroaniline 2d (142.51 mg, 1.10 mmol) and triethylamine (335.08 mg, 3.31 mmol) were dissolved in 10 mL of tetrahydrofuran, followed by addition of bis(trichloromethyl)carbonate (114.64 mg, 386.33 mol) at 0°C. The reaction solution was warmed up slowly to room temperature, and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 2e (100 mg, yield: 26.9%).
MS m/z (ESI): 337.4 [M+1]. Step 4 (R)-N5-(3,4-Difluorophenyl)-N 3-(1,1,1-trifluoropropan-2-yl)-6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-dicarboxamide 2 Compound 2e (100 mg, 297.36 mol) and compound le (133.40 mg, 892.08 mol) were dissolved in 20 mL of tetrahydrofuran, followed by dropwise addition of 4.46 mL of a IM solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran at 0°C. After completion of the addition, the reaction solution was warmed up slowly to room temperature, and stirred for 3 hours. The reaction solution was added with 2 mL of saturated ammonium chloride solution and 10 mL of water, and extracted with ethyl acetate (20 mLx2). The organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A. The resulting crude product was purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 2 (15 mg, yield: 12.1%). MS m/z (ESI): 418.2 [M+1]. 1H NMR (400MHz, CD 30D) 6 8.07 (s, 1H), 7.51-7.46 (m, 1H), 7.22-7.16 (m, 2H), 5.05 (s, 2H), 4.88-4.82 (m, 1H), 4.29-4.26 (m, 2H), 4.05-4.02 (m, 2H), 1.42-1.40 (m, 3H).
Example 3 (R)-N7-(3-Cyano-4-fluorophenyl)-N-(1,1,1-trifluoropropan-2-yl)-5,6-dihydroimidazo[1 ,5-a]pyrazine-1,7(8H)-dicarboxamide 3 F O. H F N~-N N N N H NN
3 O 0 0N 0 0tp H~~ NF 0 N Se O N -/NF Step 2 F F OHHNF N
3a 3b 3c
F O H F F FN~
+ N N N N NH 2 Step 3 N H NON
3d 3
Step 1 Tert-butyl (R)-1-((1,1,1-trifluoropropan-2-yl)carbamoyl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H )-carboxylate 3b
7-Tert-butyl 1-methyl 5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxylate 3a (469.78 mg, 1.67 mmol, prepared according to the method disclosed in the patent application "US20110034443Al") and compound le (249.74 mg, 1.67 mmol) were dissolved in 20 mL of tetrahydrofuran under an argon atmosphere, followed by dropwise addition of 3.3 mL of a IM solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran in an ice bath. The reaction solution was warmed up to room temperature, and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 3b (130 mg, yield: 21.5%). MS m/z (ESI): 363.2 [M+1]. Step 2 (R)-N-(1,1,1-Trifluoropropan-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxa mide trifluoroacetate 3c Compound 3b (130 mg, 358.77 mol) and trifluoroacetic acid (204.54 mg, 1.79 mmol) were dissolved in 2 mL of dichloromethane successively. After stirring for 2 hours, the reaction solution was concentrated under reduced pressure to obtain the crude title compound 3c (135 mg), which was used directly in the next step without purification. Step 3 (R)-N7-(3-Cyano-4-fluorophenyl)-N-(1,1,1-trifluoropropan-2-yl)-5,6-dihydroimidazo[1 ,5-a]pyrazine-1,7(8H)-dicarboxamide 3 The crude compound 3c (50 mg, 190.67 mol), 5-amino-2-fluorobenzonitrile 3d (25.96 mg, 190.67 mol, prepared according to the known method disclosed in "Bioorganic & Medicinal Chemistry Letters, 2006, 16(19), 5176-5182") and triethylamine (28.94 mg, 286.01 mol) were dissolved in 10 mL of tetrahydrofuran, followed by addition of bis(trichloromethyl)carbonate (28.29 mg, 95.34 mol) in an ice bath. After stirring for 1 hour the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 3 (2 mg, yield: 2.5%). MS m/z (ESI): 425.1 [M+1]. 1H NMR (400 MHz, DMSO-d )6 6 9.22 (s, 1H), 8.32 (d, 1H), 7.95 (d, 1H), 7.81-7.77 (m, 2H), 7.47-7.43 (m, 1H), 4.96 (s, 2H), 4.81-4.74 (m, 1H), 4.17-4.10 (m, 2H), 3.89-3.86 (m, 2H), 1.39-1.35 (dd, 3H).
Example 4 (R)-N5-(3,4,5-Trifluorophenyl)-N 3 -(,1,1-trifluoropropan-2-yl)-6,7-dihydropyrazolo[1,5 -a]pyrazine-3,5(4H)-dicarboxamide 4
F F O H F H N
' 4 F F 0 0D F 0 FeFNHO F ~la 0\ 0I F OHHN Step F NN Step2 F NN - F '-H Cr /H NN
2c 4a 4
Step 1 Methyl 5-((3,4,5-trifluorophenyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbo xylate 4a Compound 2c (100 mg, 338.74 mol), compound la (49.83 mg, 338.74 mol) and trifluoroacetic acid (342.77 mg, 3.39 mmol) were dissolved in 10 mL of tetrahydrofuran, followed by addition of bis(trichloromethyl)carbonate (35.18 mg, 118.56 3 mol) at0°C. The reaction solution was warmed up slowly to room temperature, and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 4a (50 mg, yield: 25.0%). MS m/z (ESI): 355.1 [M+1]. Step 2 (R)-N5-(3,4,5-Trifluorophenyl)-N 3 -(1,1,1-trifluoropropan-2-yl)-6,7-dihydropyrazolo[1,5 -a]pyrazine-3,5(4H)-dicarboxamide 4 Compound 4a (50 mg, 141.13 mol) and compound le (63.31 mg, 423.39 mol) were dissolved in 20 mL of tetrahydrofuran, followed by dropwise addition of 2.12 mL of a IM solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran at 0°C. After completion of the addition, the reaction solution was warmed up slowly to room temperature, and stirred for 3 hours. The reaction solution was added with 2 mL of saturated ammonium chloride solution and 10 mL of water, and extracted with ethyl acetate (20 mLx2). The organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A. The resulting crude product was purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 4 (5 mg, yield: 4%). MS m/z (ESI): 436.0 [M+1]. 1HNMR (400 MHz, CD 30D) 6 8.07 (s, 1H), 7.30-7.26 (m, 2H), 5.04 (s, 2H), 4.88-4.82 (m,1H), 4.28-4.26 (m, 2H), 4.04-4.01 (m, 2H), 1.42-1.40 (m, 3H).
Example 5
(R)-N7 -(3,4-Difluorophenyl)-N -(1,1,1-trifluoropropan-2-yl)-5,6-dihydroimidazo[1,5-a] pyrazine-1,7(8H)-dicarboxamide 5 F O H F F N F
H N
5 0 F 0 F 0 H F HNF le F t% -N N N N N Step H NN Step3 H N
5a 5b 5
Step 1 Ethyl 7-((3,4-difluorophenyl)carbamoyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxy late 5b Ethyl 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 5a (100 mg, 512.25
[mol, prepared according to the method disclosed in the patent application "CN102464661A") and compound 2d (79.36 mg, 614.70 mol) were added to 20 mL of tetrahydrofuran, followed by addition of bis(trichloromethyl)carbonate (76.01 mg, 256.13 mol) in an ice bath. The reaction solution was warmed up to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 5b (110 mg, yield: 61.3%). MS m/z (ESI): 351.1 [M+1]. Step 2 (R)-N7 -(3,4-Difluorophenyl)-N-(1,1,1-trifluoropropan-2-yl)-5,6-dihydroimidazo[1,5-a] pyrazine-1,7(8H)-dicarboxamide 5 Compound 5b (75 mg, 214.09 mol) and compound le (48.02 mg, 321.14 mol) were added to 20 mL of tetrahydrofuran, followed by addition of lithium bis(trimethylsilyl)amide (107.47 mg, 642.27 mol) in an ice bath. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A. The resulting crude product was purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 5 (20 mg, yield: 30.4%). MS m/z (ESI): 418.2 [M+1]. 1H NMR (400 MHz, DMSO-d) 6 9.09 (s, 1H), 8.31 (d, 1H), 7.76 (s, 1H), 7.64-7.60 (m, 1H), 7.34-7.23 (m, 2H), 4.94 (s, 2H), 4.79-4.77 (m, 1H), 4.16-4.14 (m, 2H), 3.88-3.85 (m, 2H), 1.37-1.35 (dd, 3H).
Example 6 (S)-N7-(3,4-Difluorophenyl)-6-methyl-N 1 -((R)-1,1,1-trifluoropropan-2-yl)-5,6-dihydroi midazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 6 F O H F
F N N N 'F H N
6 0 0 0 0 N O NH
OH H HN1 H N N N Step Step 2 -N-N Step 3
OH 6a 6b 6c 6d
00 FC 0 F 0 HN F HOH TFN -N NJ 2dHKN.4 F Ntep5
Step 4 H NN N
6e 6f 6
Step 1 Methyl (S)-5-(((1-hydroxypropan-2-yl)(4-methoxybenzyl)amino)methyl)-1H-imidazole-4-carbo xylate 6c (S)-2-((4-Methoxybenzyl)amino)propan-1-ol 6a (34.92 g, 179.08 mmol, prepared according to the known method disclosed in "Bioorganic & Medicinal Chemistry Letters, 2015, 25(5), 1086-1091") was dissolved in 600 mL of tetrahydrofuran, then methyl 5-formylimidazole-4-carboxylate 6b (23 g, 149.23 mmol, prepared according to the method disclosed in the patent application "US2008/318935") was added, followed by addition of sodium triacetoxyborohydride (47.44 g, 223.85 mmol) in batches. After stirring for 12 hours, the reaction solution was filtrated, and the filtrate was concentrated under reduced pressure. The resulting residue was added with 600 mL of ethyl acetate, washed with water (200 mLx2), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure to obtain the crude title compound 6c (40 g), which was used directly in the next step without purification. MS m/z (ESI): 334.2 [M+1]. Step 2 Methyl (S)-7-(4-methoxybenzyl)-6-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxy late 6d The crude compound 6c (11 g, 33.03 mmol) and triphenylphosphine (12.98 g, 49.49 mmol) (Sinopharm Chemical Reagent Co., Ltd.) were dissolved in 400 mL of tetrahydrofuran, followed by slow addition of diisopropyl azodicarboxylate (10 g, 49.45 mmol, Shanghai Accela ChemBio Co., Ltd.) in an ice bath. The reaction solution was warmed up slowly to room temperature, stirred for 12 hours, and concentrated under reduced pressure. The resulting residue was added with 400 mL of ethyl acetate, washed with water (100 mLx2), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 6d (4.5 g, yield: 43.2%). MS m/z (ESI): 315.9 [M+1]. Step 3 Methyl (S)-6-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate trifluoroacetate 6e Compound 6d (0.6 g, 2.33 mmol) was dissolved in 2 mL of trifluoroacetic acid. The reaction solution was heated to 100°C in a microwave for 5 minutes, cooled to room temperature, and concentrated under reduced pressure to obtain the crude title compound 6e (0.6 g), which was used directly in the next step without purification. MS m/z (ESI): 196.1 [M+1]. Step 4 Methyl (S)-7-((3,4-difluorophenyl)carbamoyl)-6-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazi ne-I-carboxylate 6f The crude compound 6e (240 mg, 776.09 mol) was dissolved in 15 mL of tetrahydrofuran, then compound 2d (150.3 mg, 1.16 mmol) and triethylamine (314.13 mg, 3.10 mmol) were added, followed by addition of bis(trichloromethyl)carbonate (92.12 mg, 310.44 mol) in an ice bath. The reaction solution was warmed up to room temperature and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 6f (0.19 g, yield: 69.9%). MS m/z (ESI): 351.1 [M+1]. Step 5 7 (S)-N -(3,4-Difluorophenyl)-6-methyl-N-((R)-1,1,1-trifluoropropan-2-yl)-5,6-dihydroi midazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 6 Compound 6f (190 mg, 542.36 mol) was dissolved in 20mL of tetrahydrofuran, then compound le (121.66 mg, 813.54 mol) was added, followed by dropwise addition of 4 mL of aIM solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran in an ice bath. After completion of the addition, the reaction solution was stirred for 2 hours. The reaction solution was added with 10 mL of water, and extracted with ethyl acetate (20 mLx2). The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 6 (25 mg, yield: 10.6%). MS m/z (ESI): 432.1 [M+1]. 1H NMR (400 MHz, DMSO-d )6 6 9.28 (s, 1H), 8.25 (d, 1H), 7.73 (s, 1H), 7.54-7.45 (m, 1H), 7.21-7.15 (m, 2H), 5.27 (s, 1H), 4.95-4.92 (m, 1H), 4.86-4.80 (m, 2H), 4.28-4.22 (m, 2H), 1.50-1.45 (m, 3H), 1.20 (d, 3H).
Example 7
(S)-N 5-(3,4-Difluorophenyl)-6-methyl-N 3 -((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihydrop yrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 7 F O H F F N F FON N ~[F H
7
0 1 0 0 >0ON"-O F 0 OHHN00 F::
+ Step 1 Step 2 F + F Step 3
7a 7b 7c 7d 0
F 0 0 F 0 F 0 H F 0 - 0 - OH '- 0 N F N N F N N O 1 F N N F H N' Step 4 H - TN' Step 5 H
7e 7f 7
Step 1 5-Tert-butyl 3-methyl (S)-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxylate 7b Tert-butyl (S)-3-iodo-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate 7a (8.3 g, 22.85 mmol, prepared according to the method disclosed in the patent application "W02016113273Al"), palladium acetate (1.03 g, 4.57 mmol), 1,1'-bis(diphenylphosphino)ferrocene (2.53 g, 4.57 mmol) and triethylamine (9.64 mL, 68.56 mmol) were dissolved in 150 mL of methanol under a carbon monoxide atmosphere. After stirring at 55°C for 15 hours, the reaction solution was filtrated through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 7b (6.3 g, yield: 93.34%). Step 2 Methyl (S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate trifluoroacetate 7c Compound 7b (6.3 g, 21.33 mmol) was dissolved in 20mL of dichloromethane, followed by addition of trifluoroacetic acid (14.1 mL, 190.91 mmol). After stirring for 2 hours, the reaction solution was concentrated under reduced pressure to obtain the crude title compound 7c (14 g), which was used directly in the next step without purification. MS m/z (ESI): 196.1 [M+1]. Step 3 Methyl (S)-5-((3,4-difluorophenyl)carbamoyl)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyraz ine-3-carboxylate 7e The crude compound 7c (2 g, 3.23 mmol) and triethylamine (1.64 g, 16.17 mmol) were dissolved in 20 mL of dichloromethane. After stirring for 10 minutes, the reaction solution was added with 1,2-difluoro-4-isocyanatobenzene (601.87 mg, 3.88 mmol, prepared according to the known method disclosed in "European Journal of Medicinal Chemistry, 2016, 115, 1-13") in an ice bath, and reacted for 20 minutes. The reaction solution was warmed up to to room temperature, and stirred for 20 minutes. The reaction solution was purified by silica gel column chromatography with eluent systems C and A successively to obtain the title compound 7e (1 g, yield: 88.27%). MS m/z (ESI): 351.1 [M+1]. Step 4 (S)-5-((3,4-Difluorophenyl)carbamoyl)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyra zine-3-carboxylic acid 7f Compound 7e (500 mg, 1.43 mmol) and sodium hydroxide (285.45 mg, 7.14 mmol) were dissolved in 5 mL of a mixed solvent of methanol, tetrahydrofuran and water (V:V:V = 2:2:1). The reaction solution was stirred at 40°C for 1 hour, and then stirred at 35°C for 15 hours. The reaction solution was concentrated under reduced pressure, added with 10 mL of water, added dropwise with 6 M hydrochloric acid until the pH is 2, and filtrated. The filter cake was collected to obtain the crude title compound 7f (450 mg), which was used directly in the next step without purification. MS m/z (ESI): 337.4 [M+1]. Step 5 (S)-N5-(3,4-Difluorophenyl)-6-methyl-N 3 -((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihydrop yrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide7 The crude compound 7f (80 mg, 237.89 [mol), 0-(7-azabenzotriazol-1-yl)-N,N,N',N-tetramethyluronium hexafluorophosphate (67.16 mg, 285.47 mol) and N,N-diisopropylethylamine (122.98 mg, 951.55 mol) were dissolved in 3 mL of N,N-dimethylformamide, and reacted for 10 minutes. The reaction solution was added with compound le (53.36 mg, 356.83 mol), and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system C. The resulting crude product was purified by preparative high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 7 (70 mg, yield: 68.22%). MS m/z (ESI): 432.1 [M+1]. 1H NMR (400 MHz, CD 3 0D) 6 8.09 (m, 1H), 7.49-7.47 (m, 1H), 7.16-7.13 (m, 2H), 5.32 (d, 1H), 5.01-4.99 (m, 1H), 4.84-4.80 (m, 1H), 4.66 (d, 1H), 4.32-4.29 (m, 1H), 4.17 (d, 1H), 1.40 (d, 3H), 1.21 (d, 3H).
Example 8 (S)-N3-(Tert-butyl)-N5-(3,4-difluorophenyl)-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazi ne-3,5(4H)-dicarboxamide 8
F 0 0 H N F N N N H N.' N
8
F F 0 H OOH H 2NI HH + \-,N )A
Tf 8
The crude compound 7f (150 mg, 446.04 [mol), 0-(7-azabenzotriazol-1-yl)-N,N,N',N-tetramethyluroniumhexafluorophosphate(157.41 mg, 669.06 pmol) and N,N-diisopropylethylamine (230.58 mg, 1.78 mmol) were dissolved in 3 mL of N,N-dimethylformamide, and reacted for 10 minutes. The reaction solution was added with tert-butylamine (48.93 mg, 669.06 mol), and stirred for 3 hours. The reaction solution was added with 30 mL of water, and extracted with ethyl acetate (30 mLx2). The organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system C. The resulting crude product was purified by preparative high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 8 (30 mg, yield: 17.18%). MS m/z (ESI): 392.2 [M+1]. 1H NMR (400 MHz, CD 3 0D) 6 8.02 (s, 1H), 7.53-7.50 (m, 1H), 7.20-7.17 (m, 2H), 5.31 (d, 1H), 5.01-4.98 (m, 1H), 4.68 (d, 1H), 4.33-4.29 (m, 1H), 4.18 (d, 1H), 1.46 (s, 9H), 1.23 (d, 3H).
Example 9 (R)-N5-(3-Cyano-4-fluorophenyl)-N 3-(1,1,1-trifluoropropan-2-yl)-6,7-dihydropyrazolo[ 1,5-a]pyrazine-3,5(4H)-dicarboxamide 9
9
OHFHNStep 1 N N - Step 2 N OH NN NN_
2c 99 9a 9b
Step 3N
Step 1 Methyl 5-((3-cyano-4-fluorophenyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-ca rboxylate 9a Compound 2c (50 mg, 275.95 mol), compound 3d (38.56 mg, 275.95 mol) and triethylamine (279.23 mg, 2.76 mmol) were dissolved in 10 mL of tetrahydrofuran, followed by addition of bis(trichloromethyl)carbonate (32.76 mg, 110.38 mol) at 0°C. The reaction solution was warmed up slowly to room temperature, and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 9a (20 mg, yield: 21.1%). MS m/z (ESI): 344.2 [M+1]. Step 2 5-((3-Cyano-4-fluorophenyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-ca rboxylic acid 9b Compound 9a (100 mg, 291.28 mol) was dissolved in 10 mL of methanol, followed by addition of lithium hydroxide (139.52 mg, 5.83 mmol) and 2 mL of water. After stirring for 3 hours, the reaction solution was concentrated under reduced pressure, added with 10 mL of water, and added dropwise with 6 M hydrochloric acid until the pH is 2. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 9b (95.91 mg), which was used directly in the next step without purification. MS m/z (ESI): 330.1 [M+1]. Step 3 (R)-N5-(3-Cyano-4-fluorophenyl)-N 3-(1,1,1-trifluoropropan-2-yl)-6,7-dihydropyrazolo[ 1,5-a]pyrazine-3,5(4H)-dicarboxamide 9 The crude compound 9b (95.91 mg, 291.28 mol) was dissolved in 10 mL of NN-dimethylformamide, then compound le (34.34 mg, 303.69 mol) and triethylamine (92.19 mg, 911.06 [mol) were added, followed by addition of O-(7-azabenzotriazol-1-yl)-N,N,NN-tetramethyluronium hexafluorophosphate (85.74 mg, 364.43 mol) at 0°C. After stirring for 12 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 9 (5 mg, yield: 3.88%). MS m/z (ESI): 425.1 [M+1]. 1H NMR (400 MHz, CD 3 0D) 6 8.07 (s, 1H), 7.87-7.85 (m, 2H), 7.32-7.27 (m, 1H), 5.06 (s, 2H), 4.86-4.84 (m, 1H), 4.29-4.27 (m, 2H), 4.06-4.03 (m, 2H), 1.42 (d, 3H).
Example 10 (S)-N 3-(Tert-butyl)-6-methyl-N5-(3,4,5-trifluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyra zine-3,5(4H)-dicarboxamide 10
F
0 N
FAN 'kN"- H H NN 10 F 0F F0 F 00 \ 0\F F OH HN + F N N F . N' Step 1 H . N' Step 2 N N F NH 2 ~ 7c la 10a
F F F F 0FO H
H Step F N N N
10b 10
Step 1 Methyl (S)-6-methyl-5-((3,4,5-trifluorophenyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr azine-3-carboxylate 10a Compound la (1.17 g, 7.92 mmol) and compound 7c (1.63 g, 5.28 mmol) were dissolved in 30 mL of dichloromethane, followed by addition of triethylamine (2.14 g, 21.22 mmol) and bis(trichloromethyl)carbonate (626.8 mg, 2.11 mmol). After stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 10a (730 mg, yield: 37.5%). MS m/z (ESI): 369.1 [M+1]. Step 2 (S)-6-Methyl-5-((3,4,5-trifluorophenyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr azine-3-carboxylic acid 10b Compound 10a (730 mg, 1.98 mmol) and sodium hydroxide (396.45 mg, 9.91 mmol) were dissolved in 10 mL of a mixed solvent of methanol, tetrahydrofuran and water (V:V:V = 2:2:1). The reaction solution was stirred at 40°C for 1 hour, and then stirred at 35°C for 15 hours. The reaction solution was concentrated under reduced pressure, added with 10 mL of water, added dropwise with 6 M hydrochloric acid until the pH is 2, and filtrated. The filter cake was collected to obtain the crude title compound 10b (702 mg, 1.98 mmol), which was used directly in the next step without purification. MS m/z (ESI): 355.4 [M+1]. Step 3 (S)-N 3-(Tert-butyl)-6-methyl-N5-(3,4,5-trifluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyra zine-3,5(4H)-dicarboxamide10 The crude compound 10b (85 mg, 239.92 [mol),
O-(7-azabenzotriazol-1-yl)-N,N,N',N-tetramethyluronium hexafluorophosphate (67.74 mg, 287.91 [mol), NN-diisopropylethylamine (129.21 mg, 719.76 [mol) were dissolved in 3 mL of N,N-dimethylformamide, and reacted for 10 minutes. The reaction solution was added with tert-butylamine (35.09 mg, 479.84 mol), and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system C. The resulting crude product was purified by preparative high performance liquid chromatography (Waters-2767, elution ammonium bicarbonate, system: water, acetonitrile) to obtain the title compound 10 (50 mg, yield: 50.90%). MS m/z (ESI): 410.2 [M+1]. 1H NMR (400 MHz, CD 3 0D) 6 8.00 (s, 1H), 7.30-7.28 (m, 2H), 5.31 (d, 1H), 4.98-4.96 (m, 1H), 4.69 (d, 1H), 4.31-4.27 (m, 1H), 4.17 (d, 1H), 1.44 (s, 9H), 1.22 (d, 3H).
Example 11 (S)-N7 -(3-Cyano-4-fluorophenyl)-6-methyl-N 1 -((R)-1,1,1-trifluoropropan-2-yl)-5,6-dihy droimidazo[1,5-a]pyrazine-1,7-(8H)-dicarboxamide11 F 0 0
N1N NN N N H -N
11
0 F 0 0 F 0 0O F,3dII0O HN Step N N NN - O N N H N Step NHN -- N NJ - NJ
6e 11a 11b
F 0 0. H le 0N F
Step3 N N
11
Step 1 Methyl (S)-7-((3-cyano-4-fluorophenyl)carbamoyl)-6-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]p yrazine-1-carboxylate 11a The crude compound 6e (9.2 g, 47.13 mmol) was dissolved in 50 mL of tetrahydrofuran, then compound 3d (6.5 g, 47.13 mmol) and triethylamine (5.82 g, 56.55 mmol) were added, followed by addition of bis(trichloromethyl)carbonate (4.9 g, 16.49 mmol) at 0°C. The reaction solution was warmed up slowly to room temperature and stirred for 12 hours. The reaction solution was filtrated, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 11a (16.84 g), which was used directly in the next step without purification. MS m/z (ESI): 358.1 [M+1].
Step 2 (S)-7-((3-Cyano-4-fluorophenyl)carbamoyl)-6-methyl-5,6,7,8-tetrahydroimidazo[1,5-a] pyrazine-l-carboxylic acid 11b The crude compound 11a (16.84 g, 47.13 mmol) was dissolved in 50 mL of methanol, followed by dropwise addition of a pre-formulated sodium hydroxide solution (dissolving sodium hydroxide (12 g, 282.76 mmol) in 60 mL of water) at0°C. The reaction solution was warmed up slowly to room temperature, and stirred for 4 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent. The resulting residue was washed with dichloromethane, and the pH of the aqueous phase was adjusted to 1-2 with 6 M hydrochloric acid. The solution was concentrated under reduced pressure to obtain the crude title compound 11b (16.18 g), which was used directly in the next step without purification. MS m/z (ESI): 344.1 [M+1]. Step 3 (S)-N7 -(3-Cyano-4-fluorophenyl)-6-methyl-N 1 -((R)-1,1,1-trifluoropropan-2-yl)-5,6-dihy droimidazo[1,5-a]pyrazine-1,7-(8H)-dicarboxamide 11 The crude compound 11b (13 g, 37.87 mmol), compound le (7.4 g, 49.23 mmol) and triethylamine (11.6 g, 113.6 mmol) were dissolved in 200 mL of N,N-dimethylformamide. After cooling to 0C, the reaction solution was added with 0-(7-azabenzotriazol-1-yl)-N,N,N-tetramethyluronium hexafluorophosphate (29 g, 75.73 mmol). The reaction solution was warmed up slowly to room temperature, and stirred for 12 hours. The reaction solution was added with 300 mL of ethyl acetate, and washed with water (100 mLx3). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 11 (1.8 g, yield: 10.8%). MS m/z (ESI): 439.0 [M+1]. 1H NMR (400 MHz, CD 3 0D) 6 7.87-7.85 (m, 1H), 7.73-7.70 (m, 2H), 7.69-7.27 (m, 1H), 5.30-5.26 (d, 1H), 4.83-4.82 (m, 1H), 4.85-4.72 (m, 2H), 4.23-4.21 (m, 2H), 1.43 (d, 3H), 1.20 (d, 3H).
Example 12 7 (S)-N-(Tert-butyl)-N -(3,4-difluorophenyl)-6-methyl-5,6-dihydroimidazo[1,5-a]pyrazin e-1,7-(8H)-dicarboxamide 12 F O H
F aN NN H . NN
12
F 0 F O H
F: NIN F N N N H . H
6f 12
Compound 6f (2.11 g, 6.27 mmol) was dissolved in 15 mL of tetrahydrofuran, then tert-butylamine (600 mg, 8.16 mmol) was added, followed by dropwise addition of a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (5 g, 31.37 mmol) at 0°C. After stirring for 2 hours, the reaction solution was added with 100 mL of water, and extracted with ethyl acetate (100 mLx3). The organic phases were combined, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 12 (120 mg, yield: 4.9%). MS m/z (ESI): 392.1 [M+1]. 1H NMR (400 MHz, CD 3 0D) 6 7.65 (s, 1H), 7.50-7.49 (m, 1H), 7.19-7.17 (m, 2H), 5.25-5.21 (d, 1H), 4.92-4.90 (m, 1H), 4.77-4.73 (m, 1H), 4.20-4.18 (m, 2H), 1.46 (s, 9H), 1.19-1.17 (d, 3H).
Example 13 (S)-6-Methyl-N-(3-methyloxetan-3-yl)-N 7 -(3,4,5-trifluorophenyl)-5,6-dihydroimidazo[ 1,5-a]pyrazine-1,7(8H)-dicarboxamide13 F F& 0 H
F N NN H . NZ 4 N 0
13 F 0 0a F 00
OHHN StN1 F N N Step 2 F . N N H N
6e 13a
F F F 0 F. 0 H
F N N NOH H F N N H . NJN + Step 3 H ,. NN 0
13b 13c 13
Step 1 Methyl (S)-6-methyl-7-((3,4,5-trifluorophenyl)carbamoyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyr azine-1-carboxylate 13a
The crude compound 6e (140.00 mg, 452.72 mol) was dissolved in 15 mL of tetrahydrofuran, then compound la (99.89 mg, 679.08 mol) and triethylamine (183.24 mg, 1.81 mmol) were added, followed by addition of bis(trichloromethyl)carbonate (53.74 mg, 181.09 mol) at 0°C. The reaction solution was warmed up slowly to room temperature and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 13a (88 mg, yield: 52.8%). MS m/z (ESI): 369.1 [M+1]. Step 2 (S)-6-Methyl-7-((3,4,5-trifluorophenyl)carbamoyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyr azine-1-carboxylic acid 13b Compound 13a (75 mg, 203.63 mol) was dissolved in 10 mL of methanol, followed by addition of sodium hydroxide (81.45 mg, 2.04 mmol) and 2 mL of water. After stirring for 3 hours, the reaction solution was concentrated under reduced pressure to obtain the crude title compound 13b (75 mg), which was used directly in the next step without purification. MS m/z (ESI): 355.0 [M+1]. Step 3 (S)-6-Methyl-N-(3-methyloxetan-3-yl)-N 7 -(3,4,5-trifluorophenyl)-5,6-dihydroimidazo[ 1,5-a]pyrazine-1,7(8H)-dicarboxamide 13 The crude compound 13b (75 mg, 211.69 mol) was dissolved in 10 mL of N,N-dimethylformamide, then 3-methyl-3-amino-oxetane 13c (27.66 mg, 317.53 mol, Shanghai Shuya Pharmaceutical Technology Co. Ltd.) and triethylamine (64.26 mg, 635.07 [mol) were added, followed by addition o 0-(7-azabenzotriazol-1-yl)-N,N,N',N-tetramethyluronium hexafluorophosphate (99.61 mg, 423.38 mol) at 0°C. After stirring at room temperature for 12 hours., the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 13 (16 mg, yield: 17.9%). MS m/z (ESI): 424.0 [M+1]. 1H NMR (400 MHz, DMSO-d )6 8.87 (s, 1H), 8.36 (s, 1H), 7.68 (s, 1H), 7.33-7.27 (m, 2H), 5.27-5.20 (m, 1H), 4.92 (d, 2H), 4.73 (d, 2H), 4.78-4.73 (m, 1H), 4.52 (d, 2H), 4.26-4.20 (m, 2H), 1.73 (s, 3H), 1.20 (d, 3H).
Example 14 (S)-6-Methyl-N 3-(3-methyloxetan-3-yl)-N5-(3,4,5-trifluorophenyl)-6,7-dihydropyrazolo[ 1,5-a]pyrazine-3,5(4H)-dicarboxamide 14
F F N N H N
14 F F F:I 0 F& O H OH H 2N F N N -
H +FN
~H N 0 N N 4 /_ 0
10b 13c 14 The crude compound 10b (100 mg, 282.26 mol), compound 13c (36.89 mg, 423.39 mol) and N,N-diisopropylethylamine (42.84 mg, 423.39 mol) were dissolved in 10 mL of NN-dimethylformamide, followed by addition of t O-(7-azabenzotriazol-1-yl)-N,N,N -tetramethyluronium hexafluorophosphate (79.69 mg, 338.71 mol). After stirring for 1 hour, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A. The resulting crude product was purified by preparative high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 14 (80 mg, yield: 66.94%). MS m/z (ESI): 424.5 [M+1]. 1H NMR (400 MHz, DMSO-d) 8.89 (s, 1H), 8.37 (s, 1H), 7.99 (s, 1H), 7.33-7.17 (m, 2H), 5.33 (d, 1H), 5.00-4.98 (m, 1H), 4.88 (d, 2H), 4.71 (d, 1H), 4.52 (d, 2H), 4.34-4.31 (m, 1H), 4.21-4.18 (m, 1H), 1.72 (s, 3H), 1.25 (d, 3H).
Example 15 (S)-N5-(3-Cyano-4-fluorophenyl)-6-methyl-N 3-((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihy dropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 15 F 0. H F
N/0 N N N F N H N_/
15
O 0 O H F
N > ON O O-N N F - NN Step 2 - Step 3 N' Step1
7b 15a 15b
00 H F 0 0 H ~F 0H HN-r F F+ N~ F S N NH 2 Step 4 N N
15c 3d 15
Step 1
(S)-5-(Tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyrazine-3-carb oxylic acid 15a Compound 7b (525 mg, 1.78 mmol) and lithium hydroxide monohydrate (373 mg, 8.9 mmol) were dissolved in 10 mL of a mixed solvent of methanol, tetrahydrofuran and water (V:V:V = 2:2:1). After stirring for 16 hours, the reaction solution was concentrated under reduced pressure, added with 10 mL of water, added dropwise with 6 M hydrochloric acid until the pH is 2, and extracted with ethyl acetate (20 mLx2). The organic phases were combined, and concentrated under reduced pressure to obtain the crude title compound 15a (500 mg), which was used directly in the next step without purification. MS m/z (ESI): 282.2 [M+1]. Step 2 Tert-butyl (S)-6-methyl-3-(((R)-1,1,1-trifluoropropan-2-yl)carbamoyl)-6,7-dihydropyrazolo[1,5-a] pyrazine-5(4H)-carboxylate 15b The crude compound 15a (500 mg, 1.78 mmol), compound le (479 mg, 3.2 mmol) and N,N-diisopropylethylamine (360 mg, 3.56 mmol) were dissolved in 20 mL of N,N-dimethylformamide, followed by addition of O-(7-azabenzotriazol-1-yl)-N,N,NN-tetramethyluronium hexafluorophosphate (628 mg, 2.67 mmol). After stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 15b (600 mg, yield: 89.56%). MS m/z (ESI): 377.2 [M+1]. Step 3 (S)-6-Methyl-N-((R)-1,1,1-trifluoropropan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyraz ine-3-carboxamide trifluoroacetate 15c Compound 15b (500 mg, 1.33 mmol) was dissolved in 20mL of dichloromethane, followed by addition of trifluoroacetic acid (758 mg, 6.65 mmol). After stirring for 2 hours, the reaction solution was concentrated under reduced pressure to obtain the crude title compound 15c (500 mg), which was used directly in the next step without purification. MS m/z (ESI): 277.2 [M+1]. Step 4 (S)-N5-(3-Cyano-4-fluorophenyl)-6-methyl-N 3-((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihy dropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 15 The crude compound 15c (50 mg, 128 mol) was dissolved in 10 mL of tetrahydrofuran, then compound 3d (26 mg, 192 mol) and triethylamine (26 mg, 256
[mol) were added, followed by addition of bis(trichloromethyl)carbonate (13 mg, 45 pmol) at 0°C. The reaction solution was warmed up to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A. The resulting crude product was purified by preparative high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 15 (20 mg, yield: 35.61%). MS m/z (ESI): 439.2 [M+1]. 'H NMR (400 MHz, CDCl 3) 6 7.87-7.86 (m, 1H), 7.83 (s, 1H), 7.70-7.68 (m, 1H), 7.42 (s, 1H), 7.20-7.16 (m, 1H), 6.01 (d, 1H), 5.34-5.23 (m, 2H), 4.92-4.89 (m, 1H), 4.84 (d, 1H), 4.38-4.34 (m, 1H), 4.25 (d, 1H), 1.49 (d, 3H), 1.27 (d, 3H).
Example 16 (S)-N5-(2,6-Difluoropyridin-4-yl)-6-methyl-N 3-((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihy dropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 16 F
H . N
16 N N F
OH F
F HN H F NH2 StepiF N ' /- Step 2 .. N'N C 16a 16b 15c 16
Step 1 2,6-Difluoro-4-isocyanatopyridine16b 2,6-Difluoro-4-aminopyridine 16a (500 mg, 3.84 mmol) and N,N-diisopropylethylamine (583 mg,5.76mmol) were dissolved in 25 mLoftoluene, followed by addition ofbis(trichloromethyl)carbonate (297 mg, 4.61 mmol). After stirring at 110°C for 4hours, the reaction solution was concentrated under reduced pressure to obtain the crude title compound 16b (1 g), which was used directly in the next step without purification. Step 2 (S)-NW-(2,6-Difluoropyridin-4-yl)-6-methyl-N 3 -((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihy dropyrazolo[11,5-a]pyrazine-3,5(4H)-dicarboxamide 16 The crude compound15c(100 mg, 256 mol) was dissolvedin10m of dichloromethane, followed byaddition ofthe crude compound 16b (80 mg) and triethylamine (78 mg, 769 mol). After stirring for 2hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A. The resulting crude product was purified by preparative high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 16 (20 mg, yield: 18.05%).
MS m/z (ESI): 433.5 [M+1]. H NMR (400 MHz, CDCl 3) 68.19 (s, 1H), 7.84 (s, 1H), 7.31 (s, 1H), 7.10 (s, 1H), 6.05 (d, 1H), 5.34 (d, 1H), 5.27-5.25 (m, 1H), 4.90-4.88 (m, 1H), 4.84 (d, 1H), 4.38-4.34 (m, 1H), 4.28 (d, 1H), 1.48 (d, 3H), 1.29 (d, 3H).
Example 17 (R)-N5-(3,4,5-Trifluorophenyl)-N 3-(1,1,1-trifluoropropan-2-yl)-6,7-dihydro-[1,2,3]triazo
lo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 17 F
H N N N
17
FF O- F 0 OH F- F 0.
HN FNF NN -NF NN O N F N Step I H NN N Step 2 N 17a 17f 17b 17c 0
F F F F ~~~~ ~ H O H 0 OH
F N N OH-F N N Step 3 H N Step 4 H , Step 5 H N'N
17d 17e 17
Step 1 (5-((3,4,5-Trifluorophenyl)carbamoyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyrazin 3-yl)methyl acetate 17b (4,5,6,7-Tetrahydro-[1,2,3]triazolo[1,5-a]pyrazin-3-yl)methyl acetate 17a (350 mg, 2 mmol, prepared according to the known method disclosed in "Journal of Medicine Chemistry, 2014, 57(9), 3687-3706") and diisopropylethylamine (790 mg, 6 mmol) were dissolved in 20 mL of dichloromethane. After stirring for 10 minutes, the reaction solution was added with 1,2,3-trifluoro-5-isocyanatobenzene 17f (400 mg, 2 mmol, J&K Scientific Co. Ltd.) in an ice bath and reacted for 20 minutes, then warmed up to room temperature and stirred for 20 minutes. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent systems C and A to obtain the title compound 17b (190 mg, yield: 25.24%). MS m/z (ESI): 370.1 [M+1]. Step 2 3-(Hydroxymethyl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazin e-5(4H)-carboxamide 17c Compound 17b (190 mg, 0.51 mmol) was dissolved in 5 mL of a mixed solvent of methanol and water (V:V=4:1), followed by addition of lithium hydroxide (108 mg, 2.57 mmol). After stirring for 2 hours, the reaction solution was added with 20 mL of water, and extracted with ethyl acetate (15 mLx3). The organic phases were combined, and concentrated under reduced pressure to obtain the crude title compound 17c (65 mg), which was used directly in the next step without purification. MS m/z (ESI): 328.1 [M+1]. Step 3 3-Formyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-5(4H)-ca rboxamide 17d The crude compound 17c (65 mg, 0.2 mmol) was dissolved in 5 mL of dichloromethane, followed by addition of pyridinium chlorochromate (138 mg, 0.64 mmol) and silica gel (140 mg, 100-200 mesh). After stirring for 3 hours, the reaction solution was filtrated and concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 17d (30 mg, yield: 43.12%). MS m/z (ESI): 326.1 [M+1]. Step 4 5-((3,4,5-Trifluorophenyl)carbamoyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyrazine 3-carboxylic acid 17e Compound 17d (30 mg, 0.1 mmol) was dissolved in 5 mL of a mixed solvent of acetonitrile and water (V:V=3:2), followed by addition of sulfamic acid (20 mg, 0.2 mmol). After stirring for 10 minutes, the solution was added with sodium chlorite (20 mg, 0.2 mmol), and stirred for 2 hours. The reaction solution was added with 0.5 mL of saturated sodium sulfite solution and 10 mL of water successively, and extracted with ethyl acetate (10 mLx3). The organic phases were combined, and concentrated under reduced pressure to obtain the crude compound 17e (25 mg), which was used directly in the next step without purification. MS m/z (ESI): 342.1 [M+1]. Step 5 (R)-N5-(3,4,5-Trifluorophenyl)-N 3-(1,1,1-trifluoropropan-2-yl)-6,7-dihydro-[1,2,3]triazo lo[1,5-a]pyrazine-3,5(4H)-dicarboxamide17 The crude compound 17e (25 mg, 73.2 [mol), 0-(7-azabenzotriazol-1-yl)-N,N,NN-tetramethyluroniumhexafluorophosphate(35mg, 146.5 mol) and N,N-diisopropylethylamine (47 mg, 366.2 mol) were dissolved in 3 mL of N,N-dimethylformamide, and reacted for 10 minutes. The reaction solution was added with compound le (33 mg, 220 mol), and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system C to obtain the title compound 17 (5 mg, yield: 15.6%). MS m/z (ESI): 437.1 [M+1]. 1H NMR (400 MHz, CD 30D) 6 7.29-7.27 (m, 2H), 4.60 (br, 1H), 4.54 (t, 2H), 4.04 (t, 2H), 2.80 (s, 2H), 1.45 (d, 3H).
Example 18
(S)-6-Methyl-N 7-(3,4,5-trifluorophenyl)-N 1 -((R)-1,1,1-trifluoropropan-2-yl)-5,6-dihydro imidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide18 F
F N N F H N
18 In accordance with the synthetic route of Example 6, the starting compound 2d in Step 4 was replaced with the starting compound la, accordingly, the title compound 18 (2.8 mg) was prepared. MS m/z (ESI): 450.2 [M+1]. 1H NMR (400 MHz, DMSO-d )6 68.86 (s, 1H), 8.33 (d, 1H), 7.73 (s, 1H), 7.33-7.28 (m, 2H), 5.29 (d, 1H), 4.92 (d, 1H), 4.85-4.76 (m, 2H), 4.28-4.22 (m, 2H), 1.44 (d, 3H), 1.34 (d, 3H).
Example 19 N 3-(3-Methyloxetan-3-yl)-N5-(3,4,5-trifluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin e-3,5(4H)-dicarboxamide 19 F F 0 H
F N N N H N'N 0
19 F F F F 0F 0 0 F 0OH 0 OH t3c 2N FN N - ~ Stepi FI Step2 H _NN' H H '
4a 19a 19
Step 1 5-((3,4,5-Trifluorophenyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carb oxylic acid 19a Compound 4a (3 g, 8.74 mmol) was dissolved in 20 mL of methanol and 20 mL of tetrahydrofuran, followed by addition of sodium hydroxide (3.39 g, 84.67 mmol) and 10 mL of water. After stirring for 16 hours, the reaction solution was concentrated under reduced pressure, added with 20 mL of water, and added dropwise with 6 M hydrochloric acid until the pH is 2. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 19a (100 mg), which was used directly in the next step without purification. MS m/z (ESI): 341.1 [M+1]. Step 2 N 3-(3-Methyloxetan-3-yl)-N5-(3,4,5-trifluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin e-3,5(4H)-dicarboxamide 19
The crude compound 19a (100 mg, 293.90 [mol), 0-(7-azabenzotriazol-1-yl)-N,N,N',N-tetramethyluronium hexafluorophosphate (69.14 mg, 293.90 mol) and triethylamine (29.74 mg, 293.90 mol) were dissolved in 5 mL of N,N-dimethylformamide, and reacted for 10 minutes. The reaction solution was added with compound 13c (108.96 mg, 881.69 mol), and stirred for 3 hours. The reaction solution was added with 10 mL of water, and extracted with ethyl acetate (20 mLx2). The organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system C. The resulting crude product was purified by preparative high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 19 (20 mg, yield: 16.62%). MS m/z (ESI): 410.1 [M+1]. 1H NMR (400 MHz, CD 3 0D) 6 7.95 (s, 1H), 7.30-7.26 (m, 2H), 5.01 (s, 2H), 4.88 (d, 2H), 4.50 (d, 2H), 4.28-4.25 (m, 2H), 4.04-4.01 (m, 2H), 1.71 (s, 3H).
Example 20 (S)-N7-(2,6-Difluoropyridin-4-yl)-6-methyl-N-((R)-1,1,1-trifluoropropan-2-yl)-5,6-dihy droimidazo[1,5-a]pyrazine-1,7-(8H)-dicarboxamide 20 F 0 H F
F N N N F H . N
20
In accordance with the synthetic route of Example 6, the starting compound 2d in Step 4 was replaced with the starting compound 2,6-difluoro-4-pyridylamine (Shanghai Bide Pharmatech Ltd.), accordingly, the title compound 20 (10 mg) was prepared. MS m/z (ESI):433.1 [M+1]. 1H NMR (400 MHz, CD 3 0D) 6 7.69 (s, 1H), 7.11-7.09 (d, 2H), 5.33-5.29 (m, 1H), 4.97-4.77 (m, 1H), 4.56-4.41 (m, 1H), 4.27-4.21 (m, 1H), 3.80-3.45 (m, 2H), 1.38 (d, 3H), 1.15 (d, 3H).
Example 21 (R)-N 3-(Sec-butyl)-N5-(3,4,5-trifluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4 H)-dicarboxamide 21 F F O H
F>NN N H
21
F F H H
19a 21
The crude compound 19a (96 mg, 282.26 mol) was dissolved in 10 mL of N,N-dimethylformamide, then (R)-but-2-amine (20.64 mg, 282.26 mol, TCI (Shanghai) Development Co., Ltd.) and triethylamine (85.69 mg, 846.78 mol) were added, followed by addition of O-(7-azabenzotriazol-1-yl)-NN,N,N'-tetramethyluronium hexafluorophosphate (79.69 mg, 338.71 mol) at 0°C. The reaction solution was warmed up to room temperature and reacted for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 21 (10 mg, yield: 8.96%). MS m/z (ESI): 396.1 [M+1]. 1H NMR (400 MHz, CD 30D) 6 8.00 (s, 1H), 7.30-7.26 (m, 2H), 5.04 (s, 2H), 4.27-4.25 (m, 2H), 4.04-4.00 (m, 3H), 1.60-1.56 (m, 2H), 1.22 (d, 3H), 0.96 (t, 3H).
Example 22 (S)-N3-((R)-Sec-butyl)-N5-(3,4-difluorophenyl)-6-methyl-6,7-dihydropyrazolo[1,5-a]pyr azine-3,5(4H)-dicarboxamide 22 F 0 H
F~0~ N H . NN
22
In accordance with the synthetic route of Example 7, the starting compound le was replaced with the starting compound (R)-but-2-amine, accordingly, the title compound 22 (20 mg) was prepared. MS m/z (ESI): 392.1 [M+1]. 1H NMR (400 MHz, CDCl3) 6 7.69 (s, 1H), 7.53-7.50 (m, 1H), 7.23 (s, 1H), 7.06-7.02 (m, 2H), 5.62 (d, 1H), 5.23 (d, 2H), 4.82 (d, 1H), 4.31-4.28 (m, 1H), 4.28 (d, 1H), 4.07 (d, 1H), 1.60-1.57 (m, 2H), 1.22 (d, 6H), 0.99 (t, 3H).
Example 23 (S)-N 5-(3,4-Difluorophenyl)-N 3-isopropyl-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine -3,5(4H)-dicarboxamide 23 F NH Nk N
H . N
23
In accordance with the synthetic route of Example 7, the starting compound le in Step 5 was replaced with the starting compound isopropylamine, accordingly, the title compound 23 (25 mg) was prepared. MS m/z (ESI): 378.1 [M+1]. 'H NMR (400 MHz, CD 3 0D) 6 8.00 (s, 1H), 7.50-7.45 (m, 1H), 7.18-7.14 (m, 2H), 5.35-5.30 (m, 1H), 4.99-4.95 (m, 1H), 4.69-4.62 (m, 1H), 4.32-4.22 (m, 1H), 4.22-4.12 (m, 2H), 1.23-1.16 (m, 9H).
Example 24 (S)-N5-(3,4-Difluorophenyl)-N 3-(1-methoxy-2-methylpropan-2-yl)-6-methyl-6,7-dihydr opyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide24 F O H
F N N N H
24
In accordance with the synthetic route of Example 7, the starting compound le in Step 5 was replaced with the starting compound 1-methoxy-2-methylpropane-2-amine (Sinopharm Chemical Reagent Co., Ltd. (Shanghai)), accordingly, the title compound 24 (15 mg) was prepared. MS m/z (ESI): 422.1 [M+1]. 1H NMR (400 MHz, CDCl 3) 6 7.69 (s, 1H), 7.56-7.51 (m, 1H), 7.15-7.09 (m, 3H), 6.13 (s, 1H), 5.26-5.22 (m, 1H), 5.20 (d, 1H), 4.85 (d, 1H), 4.36-4.32 (m, 1H), 4.22 (d, 1H), 3.47 (s, 3H), 3.44 (s, 2H), 1.50 (s, 6H), 1.25 (d, 3H).
Example 25 (S)-N-(3-Chloro-2-fluoropyridin-4-yl)-6-methyl-N 3-((R)-1,1,1-trifluoropropan-2-yl)-6,7 -dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide25
F N N H N_/ ci ,.. N'
25 In accordance with the synthetic route of Example 3, the starting compound 3a in Step 1 was replaced with the starting compound 7b, the starting compound 3d in Step 3 was replaced with the starting compound 2-chloro-3-fluoropyridine-4-amine (Shanghai Bide Pharmatech Ltd.), accordingly, the title compound 25 (20 mg) was prepared. MS m/z (ESI): 449.1 [M+1]. 1H NMR (400 MHz, CD 3 0D) 68.09 (s, 1H), 8.04 (d, 1H), 7.87 (t, 1H), 5.42 (d, 1H), 5.02 (t, 1H), 4.84 (t, 1H), 4.77 (d, 1H), 4.38-4.35 (m, 1H), 4.21 (d, 1H), 1.41 (d, 3H), 1.29 (d, 3H).
Example 26 7 (R)-N-(Sec-butyl)-N -(3,4,5-trifluorophenyl)-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8 H)-dicarboxamide 26 F F 0 H
F NN N H N-N
26
In accordance with the synthetic route of Example 1, the starting compound le in Step 3 was replaced with the starting compound (R)-but-2-amine, accordingly, the title compound 26 (4 mg) was prepared. MS m/z (ESI): 396.2 [M+1]. 1H NMR (400 MHz, CD 30D) 6 7.68 (s, 1H), 7.31-7.29 (m, 2H), 5.05 (s, 2H), 4.23-4.21 (m, 2H), 4.01-3.95 (m, 3H), 1.61-1.58 (m, 2H), 1.24-1.23 (m, 3H), 0.96 (t, 3H).
Example 27 (S)-N3 -(Tetrahydrofuran-3-yl)-N5-(3,4,5-trifluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyr azine-3,5(4H)-dicarboxamide27 F F O H N F N 0N H N' 0 27 F F F 0 OH aOH H2 N N
FHNCI*40 F 41iI H NN H N 0' 19a 27a 27 The crude compound 19a (100 mg, 293.90 [mol), 0-(7-azabenzotriazol-1-yl)-N,N,N',N-tetramethyluroniumhexafluorophosphate(138.29 mg, 587.79 mol) and triethylamine (148.70 mg, 1.47 mmol) were dissolved in 3 mL of N,N-dimethylformamide, and reacted for 10 minutes. The reaction solution was added with (S)-tetrahydrofuran-3-amine hydrochloride 27a (72.64 mg, 587.79 mol, Shanghai Bide Pharmatech Ltd.), and stirred for 3 hours. The reaction solution was added with 10 mL of water, and extracted with ethyl acetate (20 mLx2). The organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system C. The resulting crude product was purified by preparative high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 27 (20 mg, yield: 16.62%). MS m/z (ESI): 410.1 [M+1].
H NMR (400 MHz, CD 30D) 6 8.02 (s, 1H), 7.30-7.26 (m, 2H), 5.03 (s, 2H), 4.56-4.55 (m, 1H), 4.27-4.25 (m, 2H), 4.04-3.95 (m, 4H), 3.85-3.84 (m, 1H), 3.72-3.71 (m, 1H), 2.32-2.27 (m, 1H), 2.02-1.96 (m, 1H).
Example 28 (S)-N5 -(3,4-Difluorophenyl)-N 3-(1-hydroxy-2-methylpropan-2-yl)-6-methyl-6,7-dihydro pyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 28 F 0 H
F NOH HO H N 28 In accordance with the synthetic route of Example 7, the starting compound le in Step 5 was replaced with the starting compound 2-amino-2-methylpropane-1-ol (Accela ChemBio Inc), accordingly, the title compound 28 (10 mg) was prepared. MS m/z (ESI): 408.1 [M+1]. 1H NMR (400MHz, CDCl3) 6 7.70 (s, 1H), 7.57-7.52 (m, 1H), 7.16-7.10 (m, 3H), 5.94 (s, 1H), 5.25-5.23 (m, 1H), 5.22 (d, 1H), 4.83 (d, 1H), 4.59-4.58 (m, 1H), 4.37-4.32 (m, 1H), 4.21 (d, 1H), 3.77-3.69 (m, 2H), 1.45 (s, 6H), 1.25 (d, 3H).
Example 29 (R)-N5-(3,4-Difluorophenyl)-2-methyl-N 3 -(1,1,1-trifluoropropan-2-yl)-6,7-dihydropyraz olo[1,5-a]pyrazine-3,5(4H)-dicarboxamide29
F N HH N, F H Nr
29 0 HO N 1 C N H N N HNNN N F HNN Step1I Step 2 Step 3 N~~Stp 29a 29b 29c 29d 0 /0 F 0 H F Br 0\ 0\ 0 N N - F a N 1N K1 -HN
N tep5 "KNN Stp -'NZ N 29e 29f 29g 29
Step 1 2-(Benzyl((3-methyl-1H-pyrazol-5-yl)methyl)amino)ethan-1-ol29b 3-Methyl-1H-pyrazole-5-carbaldehyde 29a (5.1 g, 45.41 mmol, Shanghai Bide Pharmatech Ltd.) was dissolved in 100 mL of dichloromethane, followed by addition of 2-(benzylamino)ethanol (6.87 g, 45.41 mmol). After stirring for 1 hours, the reaction solution was added with sodium borohydride acetate (9.62 g, 45.41 mmol), and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent systems
C and A to obtain the title compound 29b (11 g, yield: 98.75%). MS m/z (ESI): 246.1 [M+1]. Step 2 N-Benzyl-2-chloro-N-((3-methyl-1H-pyrazol-5-yl)methyl)ethan-1-amine 29c Compound 29b (11 g, 44.84 mmol) was dissolved in 200mL of dichloromethane. After cooling to 0°C, the reaction solution was added dropwise with dichlorosulfoxide (16.00 g, 134.52 mmol), and reacted at 40°C for 16 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to obtain the crude title compound 29c (11.8 g), which was used directly in the next step without purification. MS m/z (ESI): 264.1 [M+1]. Step 3 5-Benzyl-2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 29d The crude compound 29c (11.8 g, 44.74 mmol) was dissolved in 200 mL of acetonitrile. After cooling to 0°C, the reaction solution was added with triethylamine (46 g, 447.37 mmol), and reacted at 80°C for 16 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was added with 100 mL of water, and extracted with ethyl acetate (200 mLx2). The organic phases were combined, and concentrated under reduced pressure obtain the crude title compound 29d (10.17g), which was used directly in the next step without purification. MS m/z (ESI): 228.1 [M+1]. Step 4 5-Benzyl-3-bromo-2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 29e The crude compound 29d (228 mg, 1.0 mmol) was dissolved in 10 mL of acetonitrile, followed by addition of N-bromosuccinimide (180 mg, 1.0 mmol) at0°C. The reaction solution was warmed up slowly to room temperature, and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 29e (185 mg, yield: 60.6%). MS m/z (ESI):306.1 [M+1]. Step 5 Methyl 5-benzyl-2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate 29f Dicobalt octacarbonyl (226 mg, 662 mol) and potassium carbonate (457 mg, 3.31 mmol) were added to 10 mL of methanol under a carbon monoxide atmosphere. After stirring at 60°C for 45 minutes, the reaction solution was added with compound 29e (100 mg, 327 mol) and methyl 2-chloroacetate (215 mg, 1.98 mmol), and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, added with 100 mL of ethyl acetate, filtrated, and washed with 100 mL of ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 29f (60 mg, yield: 64.39%).
MS m/z (ESI):286.2 [M+1]. Step 6 Methyl 2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate 29g Compound 29f (60 mg, 210.28 mol) was dissolved in 10 mL of methanol under a hydrogen atmosphere, followed by addition of palladium-carbon hydrogenation catalyst (wet) (22.38 mg, 210.28 mol). After stirring for 16 hours, the reaction solution was filtrated. The filtrate was concentrated under reduced pressure to obtain the crude title compound 29g (30 mg), which was used directly in the next step without purification. MS m/z (ESI):196.2 [M+1]. In accordance with the synthetic route of Example 2, the starting compound 2c in Step 3 was replaced with the crude starting compound 29g, accordingly, the title compound 29 (10 mg) was prepared. MS m/z (ESI): 432.2[M+1]. 1H NMR (400MHz, CD 30D) 6 7.49-7.44 (m, 1H), 7.19-7.14 (m, 2H), 4.96 (s, 2H), 4.87-4.83 (m, 1H), 4.20-4.17 (m, 2H), 4.01-3.96 (m, 2H), 2.40(s, 3H), 1.42-1.39 (m, 3H).
Example 30 Nl-(3-Methyloxetan-3-yl)-N 7-(3,4,5-trifluorophenyl)-5,6-dihydroimidazo[1,5-a]pyrazin e-1,7(8H)-dicarboxamide 30 F F 0 H 0 F H N N 0
30
In accordance with the synthetic route of Example 1, the starting compound le in Step 5 was replaced with the starting compound 13c, accordingly, the title compound 30 (5 mg) was prepared. MS m/z (ESI): 410.0 [M+1]. 1H NMR (400MHz, DMSO-d) 68.39 (s, 1H), 7.80 (s, 1H), 7.67 (s, 1H), 7.31-7.26 (m, 2H), 5.02 (s, 2H), 4.54-4.51 (d, 2H), 4.23-4.20 (m, 2H), 3.96-3.93 (m, 2H), 3.57-3.53 (m, 2H), 1.72 (s, 3H).
Example 31 (R)-N5-(3,4-Difluorophenyl)-N 3-(1,1,1-trifluoropropan-2-yl)-6,7-dihydro-[1,2,3]triazolo
[1,5-a]pyrazine-3,5(4H)-dicarboxamide 31 F O H F
N I H N 'N
31
In accordance with the synthetic route of Example 17, the starting compound 17f in Step 1 was replaced with the starting compound 7d, accordingly, the title compound 31 (20 mg) was prepared. MS m/z (ESI): 419.1 [M+1]. 'H NMR (400 MHz, CDCl 3) 6 8.11 (s, 1H), 8.09 (s, 1H), 7.56-7.52 (m, 1H), 7.13-7.08 (m, 1H), 7.06 (br, 1H), 5.35-5.32 (m, 1H), 4.99 (s, 1H), 4.94 (s, 1H), 4.68 (s, 2H), 2.26 (t, 2H), 1.42 (d, 3H).
Example 32 (R)-N7 -(2,6-Difluoropyridin-4-yl)-N-(1,1,1-trifluoropropan-2-yl)-5,6-dihydroimidazo[1 ,5-a]pyrazine-1,7(8H)-dicarboxamide 32 F
F N N F H N
32
In accordance with the synthetic route of Example 16, the starting compound 15c in Step 2 was replaced with the starting compound 3c, accordingly, the title compound 32 (25 mg) was prepared. MS m/z (ESI): 419.1 [M+1]. 1H NMR (400 MHz, DMSO-d) 6 8.79 (s, 1H), 8.33 (s, 1H), 7.70 (s, 1H), 7.10 (s, 2H), 5.08 (s, 2H), 4.84-4.80 (m, 1H), 4.26-4.23 (m, 2H), 3.99-3.96 (m, 2H), 1.44 (d, 3H).
Example 33 (S)-6-Methyl-N5-(3,4,5-trifluorophenyl)-N 3-((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihydro pyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 33 F F H F
F N N N r F H N'
33
In accordance with the synthetic route of Example 7, the starting compound 7d in Step 3 was replaced with compound 17f, accordingly, the title compound 33 (20 mg) was prepared. MS m/z (ESI): 450.0 [M+1]. 1H NMR (400 MHz, CD 3 0D) 6 8.09 (s, 1H), 7.30-7.27 (m, 2H), 5.36 (d, 1H), 4.98-4.95 (m, 1H), 4.83-4.80 (m, 1H), 4.70 (d, 1H), 4.31-4.27 (m, 1H), 4.20 (d, 1H), 1.41 (d, 3H), 1.22 (d, 3H).
Example 34 (S)-N5-(3,4-Difluorophenyl)-6-methyl-N 3 -((S)-tetrahydrofuran-3-yl)-6,7-dihydropyrazo o[1,5-a]pyrazine-3,5(4H)-dicarboxamide34 F O H F ~0 N Nn H N' 0
34 F ~O F 0 O H N OH N F H, N - 4 N_~NN H0
7f 34 The crude compound 7f mg, (150 446.04 [mol), O-(7-azabenzotriazol-1-yl)-NN,N',N-tetramethyluroniumhexafluorophosphate(157.41 mg, 669.06 pmol) and N,N-diisopropylethylamine (230.58 mg, 1.78 mmol) were dissolved in 3 mL of N,N-dimethylformamide, and reacted for 10 minutes. The reaction solution was added with compound 27a (82.3 mg, 669.06 mol), and stirred for 3 hours. The reaction solution was added with 30 mL of water, and extracted with ethyl acetate (30 mLx2). The organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system C. The resulting crude product was purified by preparative high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 34 (30 mg, yield: 16.54%). MS m/z (ESI): 406.2 [M+1]. 1H NMR (400 MHz, CD 3 0D) 6 8.05 (s, 1H), 7.52-7.47 (m, 1H), 7.20-7.17 (m, 2H), 5.33 (d, 1H), 5.00-4.99 (m, 1H), 4.70 (d, 1H), 4.56-4.54 (m, 1H), 4.34-4.32 (m, 1H), 4.21-4.20 (m, 1H), 4.04-3.95 (m, 2H), 3.85-3.83 (m, 1H), 3.73-3.72 (m, 1H), 2.32-2.27 (m, 1H), 2.01-1.94 (m, 3H), 1.24 (d, 1H).
Example 35 Nl-(3-Methyltetrahydrofuran-3-yl)-N 7 -(3,4,5-trifluorophenyl)-5,6-dihydroimidazo[1,5-a ]pyrazine-1,7-(8H)-dicarboxamide 35 F
F N N - N0 H N 6 N
35 In accordance with the synthetic route of Example 1, the starting compound le in Step 5 was replaced with the starting compound 3-methyltetrahydrofuran-3-amine (Shanghai Bide Pharmatech Ltd.), accordingly, the title compound 35 (16 mg) was prepared. MS m/z (ESI): 424.1 [M+1]. 1H NMR (400 MHz, DMSO-d) 6 8.87 (s, 1H), 8.35 (s, 1H), 7.67 (s, 1H),
7.31-7.27 (in, 2H), 5.03 (s, 2H), 4.21 (t, 2H), 4.10 (d, 1H), 3.96-3.92 (in, 4H), 3.75 (d, 1H), 2.46-2.41 (in, 1H), 2.09-2.01 (in, 1H), 1.59 (s, 3H).
Example 36 (R)-N -(3,4-Difluorophenyl)-N 8-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrrolo[1,2-a]p 2
yrazine-2,8(1H)-dicarboxamide 36 F 0N N
F ci~ N N <~ F
36
00 0 0 F 0 0
N O HN .F N N F N N H N
36a 36b 36
Methyl pyrrolo[1,2-a]pyrazine-8-carboxylate 36a (500 mg, 2.84 mmol, prepared according to the method disclosed in the patent application "US2015/51189 Al") and palladium-carbon (698.38 mg, 2.84 mmol) were dissolved in 10 mL of methanol under a hydrogen atmosphere. After stirring for 16 hours, the reaction solution was filtrated, and concentrated under reduced pressure to obtain the crude product methyl 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate 36b (511 mg, yield: 100%). MS m/z (ESI): 181.2 [M+1]. In accordance with the synthetic route of Example 2, the starting compound 2c in Step 3 was replaced with the crude starting compound 36b, accordingly, the title compound 36 (10 mg) was prepared. MS m/z (ESI): 417.1 [M+1]. 1H NMR (400 MHz, CD3 0D) 5 7.51-7.46 (in, 1H), 7.19-7.15 (in, 2H), 6.71-6.70 (in, 2H), 5.00 (s, 2H), 4.85-4.82 (in, 1H), 4.11-4.09 (in, 2H), 3.94-3.91 (in, 2H), 1.39 (d, 3H).
Example 37 (R)-N 7-(2-(Difluoromethyl)pyridin-4-yl)-N 1 -(,1,1-trifluoropropan-2-yl)-5,6-dihydroimi dazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide37
F N N F N
37
0 N- f 0 HN4F
H2N F HN F NN F N N F N- Step1 F NJ' Step2 H N 37a 37b 37c 37
Step 1 Ethyl 7-((2-(difluoromethyl)pyridin-4-yl)carbamoyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin e-1-carboxylate 37c 2-(Difluoromethyl)pyridin-4-amine 37a (73.83 mg, 512.25 ptmol, prepared according to the method disclosed in the patent application "W2015/118057Al"), ethyl 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 37b (100 mg, 512.25 ptmol, Shanghai Bide Pharmatech Ltd.) and triethylamine (103.67 mg, 1.02 mmol) were dissolved in 10 mL of tetrahydrofuran, followed by addition of bis(trichloromethyl)carbonate (60.80 mg, 204.09 ptmol) at 0°C. The reaction solution was warmed up slowly to room temperature, and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 37c (120 mg, yield: 64.2%). MS m/z (ESI): 366.2 [M+1]. Step 2 (R)-N 7-(2-(Difluoromethyl)pyridin-4-yl)-N-(,1,1-trifluoropropan-2-yl)-5,6-dihydroimi dazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 37 Compound 37c (100 mg, 273.72 ptmol) and compound le (30.95 mg, 273.72 ptmol) were dissolved in 10 mL of tetrahydrofuran, followed by addition of 1 mL of a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran at 0°C. After completion of the addition, the solution was warmed up slowly to room temperature, and stirred for 6 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 37 (20 mg, yield: 16.9%). MS m/z (ESI): 433.2 [M+1]. 1H NMR (400 MHz, CD3 0D) 5 8.42 (d, 1H), 7.88-7.87 (m, 1H), 7.70-7.66 (m, 2H), 6.80-6.53 (m, 1H), 5.10 (s, 2H), 4.83-4.81 (m, 1H), 4.26-4.24 (m, 2H), 4.00-3.98 (m, 2H), 1.44 (d, 3H).
Example 38 (S)-N 3 ,N5 -Bis(3,4-difluorophenyl)-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H )-dicarboxamide 38 F O H F0 N F~N~Nv ~\ F H N -N F
38
F 0~ F 0 H F OH N N F2d 113L C\ F N N -F NN I
NN 01 N.-N F 7f 38
The crude 7f (80 compound mg, 237.89 [mol), 0-(7-azabenzotriazol-1-yl)-NN,N',N-tetramethyluronium hexafluorophosphate (83.95 mg, 356.83 mol) and N,N-diisopropylethylamine (92.23 mg, 713.66 mol) were dissolved in 3 mL of N,N-dimethylformamide, and reacted for 10 minutes. The reaction solution was added with compound 2d (46.07 mg, 356.83 mol), and stirred for 16 hours. The reaction solution was added with 10 mL of water, and extracted with ethyl acetate (40 mLx2). The organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system C. The resulting crude product was purified by preparative high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 38 (10 mg, yield: 9.4%). MS m/z (ESI): 448.1 [M+1]. 1H NMR (400 MHz, CD 30D) 6 8.18 (s, 1H), 7.83-7.81 (m, 1H), 7.52-7.50 (m, 1H), 7.41-7.39 (m, 1H), 7.24-7.17 (m, 3H), 5.39 (d, 1H), 5.04-5.01 (m, 1H), 4.75 (d, 1H), 4.38-4.36 (m, 1H), 4.22 (d, 1H), 1.26 (d, 3H).
Example 39 (S)-N5-(3,4-Difluorophenyl)-6-methyl-N 3 -((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihydro-[ 1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 39 F N NF
H H - NN N
39
N o tp , NH ± 0 CI Step 1 Step 2 Step 3
6a 39a 39b 39c
0 0H 0
F H OH 2d -- 0 0 _ F oNl__k F Step 4 Step 5 FN N NAN H H NN
39d 39e 39f 39
Step 1 (S)-4-((1-Hydroxypropan-2-yl)(4-methoxybenzyl)amino)but-2-yn-1-yl acetate 39b Compound 6a (3.00 g, 15.00 mmol) was dissolved in 60 mL of dioxane, followed by addition of 4-chlorobut-2-yn-1-yl acetate 39a (5.73 g, 39.00 mmol, prepared according to the known method disclosed in "Journal of Medicine Chemistry, 2014, 57(9),3687-3706") and triethylamine (4.7 g, 46.00 mmol). After stirring at 60°C for 12 hours, the reaction solution was filtrated. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 39b (2.20 g, yield: 42.2%). MS m/z (ESI): 306.2 [M+1]. Step 2 (S)-4-((1-Chloropropan-2-yl)(4-methoxybenzyl)amino)but-2-yn-1-yl acetate 39c Compound 39b (2.20 g, 7.20 mmol) and pyridine (854 mg, 10.08 mmol) were dissolved in 30 mL of dichloromethane, followed by slowly dropwise addition of thionyl chloride (1.50 g, 12.60 mmol) in an ice bath. The reaction solution was warmed up slowly to room temperature and stirred for 2 hours. The reaction solution was added with 100 mL of dichloromethane, washed with water (50 mLx2), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure to obtain the title compound 39c (2.20 g), which was used directly in the next step without purification. Step 3 (S)-(5-(4-Methoxybenzyl)-6-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyrazin-3-y 1)methyl acetate 39d The crude compound 39c (2.20 g, 6.79 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of sodium azide (574 mg, 8.83 mmol). After stirring at 80°C for 12 hours, the reaction solution was cooled to room temperature, added with 50 mL of ethyl acetate, washed with water (20 mLx2), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 39d (1.30 g, yield: 57.9%). MS m/z (ESI): 331.1 [M+1]. Step 4 (S)-(6-Methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyrazin-3-yl)methyl acetate trifluoroacetate 39e Compound 39d (1.30 g, 2.33 mmol) was dissolved in 5 mL of trifluoroacetic acid. The reaction solution was heated to 100°C in a microwave for 5 minutes, cooled to room temperature, and concentrated under reduced pressure to obtain the crude title compound 39e (1.28 g), which was used directly in the next step without purification. Step 5 (S)-(5-((3,4-Difluorophenyl)carbamoyl)-6-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5 a]pyrazin-3-yl)methyl acetate 39f The crude compound 39e (200 mg, 0.62 mmol), compound 2d (228 mg, 1.90 mmol) and triethylamine (290 mg, 2.86 mmol) were dissolved in 10 mL of tetrahydrofuran, followed by addition of bis(trichloromethyl)carbonate (87 mg, 0.3 mmol) in an ice bath. After stirring for 3 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 39f (90 mg, yield:
40.1%). MS m/z (ESI): 366.1 [M+1]. In accordance with the synthetic route of Example 17, the starting compound 17b in Step 2 was replaced with compound 39f, accordingly, the title compound 39 (20 mg) was prepared. MS m/z (ESI): 433.1 [M+1]. 'H NMR (400 MHz, CD 3 0D) 6 7.50-7.48 (m, 1H), 7.18-7.16 (m, 2H), 5.43 (d, 1H), 5.08-5.06 (m, 1H), 4.89-4.87 (m, 1H), 4.74 (d, 1H), 4.60 (d, 1H), 4.49-4.46 (m, 1H), 1.49 (d, 3H), 1.21 (d, 3H).
Example 40 (S)-N-(4-Fluoro-3-methylphenyl)-6-methyl-N 3-((R)-1,1,1-trifluoropropan-2-yl)-6,7-dih ydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 40 F F F
0 NH F NN N H N N N 40
In accordance with the synthetic route of Example 39, the starting compound 2d in Step 5 was replaced with 3-methyl-4-fluoroaniline 40a, accordingly, the title compound 40 (25 mg) was prepared. MS m/z (ESI): 429.1 [M+1]. 1H NMR (400 MHz, CD 30D) 6 7.29-7.26 (m, 1H), 7.21-7.20 (m, 1H), 6.99-6.94 (m, 1H), 5.45-5.41 (d, 1H), 5.09-5.08 (m, 2H), 4.76-4.71 (d, 1H), 4.63-4.59 (m, 1H), 4.52-4.51 (d, 1H), 2.27-2.26 (d, 3H), 1.48-1.46 (d, 3H), 1.23-1.22 (d, 3H).
Example 41 (S)-N -(3,4-Difluorophenyl)-6-methyl-N 1 -((S)-1,1,1-trifluoropropan-2-yl)-5,6-dihydroi 7
midazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 41 F 0 H F N~F F N N HN
41
In accordance with the synthetic route of Example 6, the starting compound le was replaced with the starting compound (2S)-1,1,1-trifluoropropyl-2-amine hydrochloride (Shanghai Bide Pharmatech Ltd.), accordingly, the title compound 41 (110 mg) was prepared. MS m/z (ESI): 432.1 [M+1]. 1H NMR (400 MHz, CDCl 3) 6 7.54-7.51 (m, 1H), 7.50 (s, 1H), 7.21-7.02 (m, 3H), 6.83 (s, 1H), 5.26-5.16 (m, 1H), 5.15-5.04 (m, 1H), 4.95-4.92 (m, 1H), 4.86-4.80 (m,
1H), 4.28-4.22 (m, 1H), 4.01-4.05 (m,1H), 1.48 (d, 3H), 1.20 (d, 3H).
Example 42 (R)-N5-(3,4-Difluorophenyl)-7-methyl-N 3 -((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihydro-[ 1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 42
N N F H N'N
42
In accordance with the synthetic route of Example 39, the starting compound 6a in Step 1 was replaced with the compound (2R)-1-((4-methoxybenzyl)amino)propan-1-o (prepared according to the known method disclosed in "Organic and Biomolecular Chemistry, 2014, 12, 16, 2584-2591"), accordingly, the title compound 42 (20 mg) was prepared. MS m/z (ESI): 433.1 [M+1]. 1H NMR (400 MHz, CD 3 0D) 6 7.50-7.48 (m, 1H), 7.15-7.12 (m, 2H), 5.16 (d, 1H), 5.02 (d, 1H), 4.77-4.75 (m, 1H), 4.13-4.10 (m, 1H), 3.77 (m, 1H), 3.06-3.03 (m, 1H), 1.67 (d, 3H), 1.44 (d, 3H).
Example 43 (S)-N5 -(3,4-Difluorophenyl)-6-methyl-N 3-((S)-1,1,1-trifluoropropan-2-yl)-6,7-dihydro-[ 1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 43 F 0 H F
H NN
43
N - ~ aF 0 0H F F N NF N N H - NH N
39f 43
In accordance with the synthetic route of Example 17, the starting compound 17b in Step 2 was replaced with compound 39f, and the starting compound le was replaced with the starting compound (2S)-1,1,1-trifluoropropyl-2-amine hydrochloride, accordingly, the title compound 43 (30 mg) was prepared. MS m/z (ESI): 433.3 [M+1]. 1HNMR (400 MHz, CDCl 3) 6 7.53-7.50 (m, 1H), 7.30 (d, 1H), 7.15 (dd, 1H), 7.06-7.04 (m, 1H), 6.84 (s, 1H), 5.37-5.32 (m, 1H), 5.27 (d, 1H), 4.89-4.85 (m, 2H), 4.61 (d, 1H), 4.52-4.48 (m, 1H), 1.50 (d, 3H), 1.26 (d, 3H).
Example 44 (R)-N5-(3-Cyano-4-fluorophenyl)-7-methyl-N 3-((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihy dro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 44 F 0H F
N N N H N
44 In accordance with the synthetic route of Example 39, the starting compound 6a in Step 1 was replaced with the compound (2R)-1-((4-methoxybenzyl)amino)propan-1-ol, and the starting compound 2d in Step 5 was replaced with compound 3d, accordingly, the title compound 44 (15 mg) was prepared. MS m/z (ESI): 440.3 [M+1]. 1H NMR (400 MHz, CD 30D) 6 7.86-7.84 (m, 1H), 7.73-7.70 (m, 1H), 7.29 (t, 1H), 5.19 (d, 1H), 5.05 (d, 1H), 4.85-4.82 (m, 1H), 4.12 (d, 1H), 3.77-3.73 (m, 1H), 3.64-3.62 (m, 1H), 1.69 (d, 3H), 1.46 (d, 3H).
Example 45 (S)-N5-(3-Cyano-4-fluorophenyl)-6-methyl-N 3-((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihy dro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide45 F O H F
N N)KN NkF N H H INN
45
F 0 - 0 OH 'F H 0 OH H~0U0' HN NH 2 NNN N N N O N Step1 N H N Step2 N- StNp '
39e 3d 45a 45b
F H F 0 F ~ 0 H F 0 0 OH le0N F N N N N N OH Step H N'N Step 4 N H N 'N Step 5 N H e- N 'N
45c 45d 45
Step 1 (S)-(5-((3-Cyano-4-fluorophenyl)carbamoyl)-6-methyl-4,5,6,7-tetrahydro-[1,2,3]triazol o[1,5-a]pyrazin-3-yl)methyl acetate 45a The crude compound 39e (400 mg, 1.24 mmol), compound 3d (450 mg, 3.80 mmol) and triethylamine (580 mg, 5.80 mmol) were dissolved in 20 mL of tetrahydrofuran, followed by addition of bis(trichloromethyl)carbonate (180 mg, 0.6 mmol) in an ice bath. After stirring for 3 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 45a (195 mg, yield:
40.1%). MS m/z (ESI): 373.1 [M+1]. Step 2 (S)-N-(3-Cyano-4-fluorophenyl)-3-(hydroxymethyl)-6-methyl-6,7-dihydro-[I,2,3]triazol o[1,5-a]pyrazine-5(4H)-carboxamide 45b Compound 45a (190 mg, 0.51 mmol) was dissolved in 5 mL of a mixed solvent of methanol and water (V:V=4:1), followed by addition of lithium hydroxide (108 mg, 2.57 mmol). After stirring for 2 hours, the reaction solution was added with 20 mL of water, and extracted with ethyl acetate (15 mLx3). The organic phases were combined, and concentrated under reduced pressure to obtain the crude title compound 45b (120 mg), which was used directly in the next step without purification. MS m/z (ESI): 331.2 [M+1]. Step 3 (S)-N-(3-Cyano-4-fluorophenyl)-3-formyl-6-methyl-6,7-dihydro-[1,2,3]triazolo[1,5-a]p yrazine-5(4H)-carboxamide 45c The crude compound 45b (100 mg, 0.3 mmol) was dissolved in 5 mL of dichloromethane, followed by addition of pyridinium chlorochromate (138 mg, 0.64 mmol) and silica gel (140 mg, 100-200 mesh). After stirring for 3 hours, the reaction solution was filtrated and concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 45c (60 mg, yield: 43.1%). MS m/z (ESI): 329.5 [M+1]. Step 4 (S)-5-((3-Cyano-4-fluorophenyl)carbamoyl)-6-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo
[1,5-a]pyrazine-3-carboxylic acid 45d Compound 45c (30 mg, 0.1 mmol) was dissolved in 5 mL of a mixed solvent of acetonitrile and water (V:V=3:2), followed by addition of sulfamic acid (20 mg, 0.2 mmol). After stirring for 10 minutes, the solution was added with sodium chlorite (20 mg, 0.2 mmol), and stirred for 2 hours. The reaction solution was added with 0.5 mL of saturated sodium sulfite solution and 10 mL of water successively, and extracted with ethyl acetate (10 mLx3). The organic phases were combined, and concentrated under reduced pressure to obtain the crude compound 45d (25 mg), which was used directly in the next step without purification. MS m/z (ESI): 345.2 [M+1]. Step 5 (S)-N5-(3-Cyano-4-fluorophenyl)-6-methyl-N 3-((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihy dro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide45 The crude compound 45d (20 mg, 58.0 [mol), 0-(7-azabenzotriazol-1-yl)-N,N,NN-tetramethyluroniumhexafluorophosphate(105mg, 146.5 mol) and N,N-diisopropylethylamine (150 mg, 366.2 mol) were dissolved in 3 mL of N,N-dimethylformamide, and reacted for 10 minutes. The reaction solution was added with compound le (50 mg, 110 mol), and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system C to obtain the title compound 45 (8 mg, yield: 31.3%). MS m/z (ESI): 440.3 [M+1]. 'H NMR (400 MHz, CD 30D) 6 7.87-7.84 (m, 1H), 7.73-7.70 (m, 1H), 7.29 (t, 1H), 5.45 (t, 1H), 5.08-5.06 (m, 1H), 4.92-4.89 (m, 1H), 4.77 (d, 1H), 4.62 (d, 1H), 4.50 (d, 1H), 1.46 (d, 3H), 1.21 (d, 3H).
Example 46 (S)-N7-(3-Cyano-4-fluorophenyl)-6-methyl-N 1 -(1-methylcyclobutyl)-5,6-dihydroimidaz o[1,5-a]pyrazine-1,7(8H)-dicarboxamide46
F 01 0 NNNH N N NH N H NN
46
In accordance with the synthetic route of Example 11, the starting compound le in Step 3 was replaced with the compound 1-methylcyclobutyl-1-amine (Shanghai Bide Pharmatech Ltd.), accordingly, the title compound 46 (20 mg) was prepared. MS m/z (ESI): 411.4 [M+1]. 1H NMR (400 MHz, CD 30D) 6 7.86-7.84 (m, 1H), 7.72-7.70 (m, 1H), 7.65 (s, 1H), 7.28 (t, 1H), 5.26 (d, 1H), 4.92-4.89 (m, 1H), 4.78 (d, 1H), 4.20-4.17 (m, 2H), 2.45-2.43 (m, 2H), 2.10-2.07 (m, 2H), 1.92-1.90 (m, 2H), 1.55 (s, 3H), 1.20 (d, 3H).
Example 47 (R)-N7-(3-Cyano-4-fluorophenyl)-5-methyl-N 1 -((R)-1,1,1-trifluoropropan-2-yl)-5,6-dihy droimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 47 F 0. H F
- N'N N H N
47 In accordance with the synthetic route of Example 6, the starting compound 6a in Step 1 was replaced with the starting compound (2S)-1-((4-methoxybenzyl)amino)propan-1-ol, and the starting compound 2d in Step 4 was replaced with the starting compound 3d, accordingly, the title compound 47 (12 mg) was prepared. MS m/z (ESI): 439.2 [M+1]. 1HNMR (400 MHz, CDCl3) 6 7.88 (dd, 1H), 7.62-7.61 (m, 1H), 7.57 (s, 1H), 7.22-7.17 (m, 3H), 5.20 (d, 1H), 5.03 (d, 1H), 4.84-4.80 (m, 1H), 4.42-4.40 (m, 1H),
4.25-4.21 (dd, 1H), 3.58-3.53 (dd, 1H), 1.64 (d, 3H), 1.47 (d, 3H).
Example 48 (S)-N7 -(3-Cyano-4-fluorophenyl)-6-methyl-N 1 -(1-methylcyclopropyl)-5,6-dihydroimida zo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 48
Fo7
N<N N N H N
48
In accordance with the synthetic route of Example 11, the starting compound le in Step 3 was replaced with the compound 1-methylcyclopropyl-1-amine (Shanghai Bide Pharmatech Ltd.), accordingly, the title compound 48 (20 mg) was prepared. MS m/z (ESI): 397.3 [M+1]. 1HNMR (400 MHz, CD 30D) 6 7.86-7.84 (m, 1H), 7.72-7.70 (m, 1H), 7.63 (s, 1H), 7.29 (t, 1H), 5.28 (d, 1H), 4.91-4.89 (m, 1H), 4.80 (d, 1H), 4.20-4.17 (m, 2H), 1.44 (s, 3H), 1.20 (d, 3H), 0.71-0.68 (m, 2H), 0.68-0.66 (m, 2H).
Example 49 (R)-N5-(3,4-Difluorophenyl)-6-methyl-N 3-((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihydrop yrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 49 F 0
F N N H3C H 3C N'N
49
In accordance with the synthetic route of Example 7, the starting compound 7a in Step 1 was replaced with the starting compound tert-butyl (R)-3-iodo-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (prepared according to the method disclosed in the patent application "W2017198744Al"), accordingly, the title compound 49 (20 mg) was prepared. MS m/z (ESI): 432.2 [M+1]. 1H NMR (400 MHz, CD 3 0D) 6 8.11 (m, 1H), 7.52-7.47 (m, 1H), 7.21-7.16 (m, 2H), 5.38-5.33 (d, 2H), 5.02-4.99 (m, 1H), 4.74-4.69 (d, 1H), 4.36-4.33 (m, 1H), 4.23-4.19 (d, 1H), 1.43-1.42 (d, 3H), 1.27-1.25 (d, 3H).
Example 50 (S)-N-(Tert-butyl)-N 7 -(3-cyano-4-fluorophenyl)-6-methyl-5,6-dihydroimidazo[1,5-a]py razine-1,7(8H)-dicarboxamide 50
F 0 H 0 N
NC N N N H N
50
In accordance with the synthetic route of Example 11, the starting compound le in Step 3 was replaced with the starting compound tert-butylamine (Sinopharm Chemical Reagent Co., Ltd.), accordingly, the title compound 50 (180 mg) was prepared. MS m/z (ESI): 399.2 [M+1]. 'H NMR (400 MHz, CD 3 0D) 6 7.90-7.88 (m, 1H), 7.75-7.67 (m, 1H), 7.33 (s, 1H), 7.31-7.29 (m, 1H), 5.28-5.24 (d, 1H), 4.94 (m, 1H), 4.81-4.77 (m, 1H), 4.26-4.20 (m, 2H), 1.48 (d, 9H), 1.22-1.20 (d, 3H).
Example 51 (S)-N7 -(3-Cyano-4-fluorophenyl)-N-((R)-1-fluoropropan-2-yl)-6-methyl-5,6-dihydroim idazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide51 F ~.~0 H 0 N NC N N F H , N
51
In accordance with the synthetic route of Example 11, the starting compound le in Step 3 was replaced with the starting compound (S)-2-fluoro-1-methyl-ethylamine hydrochloride (Shanghai Bide Pharmatech Ltd.), accordingly, the title compound 51 (20 mg) was prepared. MS m/z (ESI): 403.2 [M+1]. 1H NMR (400 MHz, CD 3 0D) 6 7.89-7.87 (m, 1H), 7.77-7.74 (m, 1H), 7.73 (s, 1H), 7.31-7.29 (m, 1H), 5.31-5.27 (d, 1H), 4.94-4.92 (m, 1H), 4.83-4.78 (d, 1H), 4.52-4.50 (d, 1H), 4.40-4.39 (m, 2H), 4.25-4.22 (m, 2H), 1.32-1.30 (d, 3H), 1.22-1.20 (d, 3H).
Example 52 (S)-N7-(3-Cyano-4-fluorophenyl)-6-methyl-N 1 -((S)-1,1,1-trifluoropropan-2-yl)-5,6-dihy droimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 52 F 0 H F
N/ N N F H N
52
In accordance with the synthetic route of Example 11, the starting compound le in Step 3 was replaced with the starting compound (2S)-1,1,1-trifluoropropyl-2-amine hydrochloride, accordingly, the title compound 52 (20 mg) was prepared. MS m/z (ESI): 439.2 [M+1].
H NMR (400 MHz, CDCl3) 6 7.91 (dd, 1H), 7.63-7.62 (m, 1H), 7.50 (s, 1H), 7.20-7.14 (m, 3H), 5.22-5.16 (m, 2H), 4.95 (d, 1H), 4.85-4.83 (m, 1H), 4.26-4.23 (m, 1H), 4.11-4.08 (dd, 1H), 1.48 (d, 3H), 1.26 (d, 3H).
Example 53 (R)-N7 -(3,4-Difluorophenyl)-6-methyl-N 1 -((R)-1,1,1-trifluoropropan-2-yl)-5,6-dihydroi midazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 53 F N N F
H N, N
53
In accordance with the synthetic route of Example 6, the starting compound 6a in Step 1 was replaced with the starting compound (R)-2-((4-methoxybenzyl)amino)propan-1-ol (prepared according to the known method disclosed in "Bioorganic & Medicinal Chemistry Letters, 2015, 25(5), 1086-1091"), accordingly, the title compound 53 (90 mg) was prepared. MS m/z (ESI): 432.2 [M+1]. 1H NMR (400 MHz, CD30D) 6 7.71 (s, 1H), 7.52-7.47 (m, 1H), 7.21-7.17 (m, 2H), 5.31-5.27 (d, 1H), 4.94-4.92 (m, 1H), 4.76-4.84 (m, 2H), 4.24-4.22 (m, 2H), 1.45-1.43 (d, 3H), 1.23-1.21 (d, 3H).
Example 54 (R)-N7-(3-Cyano-4-fluorophenyl)-6-methyl-N 1 -((R)-1,1,1-trifluoropropan-2-yl)-5,6-dihy droimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 54 F 0
NC NN C 'F
H3C N3
54
In accordance with the synthetic route of Example 6, the starting compound 6a in Step 1 was replaced with the starting compound (R)-2-((4-methoxybenzyl)amino)propan-1-ol, and the starting compound 2d in Step 4 was replaced with compound 3d, accordingly, the title compound 54 (88 mg) was prepared. MS m/z (ESI): 439.2 [M+1]. 1H NMR (400 MHz, CD30D) 6 7.89-7.87 (m, 1H), 7.75-7.73 (m, 1H), 7.71 (s, 1H), 7.33-7.29 (m, 1H), 5.32-5.28 (d, 1H), 4.95-4.93 (m, 1H), 4.85-4.82 (m, 2H), 4.25-4.22 (m, 2H), 1.45-1.43 (d, 3H), 1.23-1.22 (d, 3H).
Example 55 (R)-N 7-(3-Cyano-4-fluorophenyl)-6-methyl-N 1 -((S)-1,1,1-trifluoropropan-2-yl)-5,6-dihy droimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 55
F ~.~0 H F
N N'X N H N
55
In accordance with the synthetic route of Example 6, the starting compound 6a in Step 1 was replaced with the starting compound (R)-2-((4-methoxybenzyl)amino)propan-1-ol, the starting compound 2d in Step 4 was replaced with compound 3d, and the starting compound le in Step 5 was replaced with the starting compound (2S)-1,1,1-trifluoropropyl-2-amine hydrochloride, accordingly, the title compound 55 (20 mg) was prepared. MS m/z (ESI):439.2 [M+1]. 'H NMR (400 MHz, CDCl3) 6 7.86 (dd, 1H), 7.70-7.65 (m, 2H), 7.30-7.26 (m, 3H), 5.30 (d, 1H), 4.94-4.93 (m, 1H), 4.81-4.76 (m, 2H), 4.26-4.17 (m, 2H), 1.43 (d, 3H), 1.20 (d, 3H).
Example 56 (S)-N7 -(3-Cyano-4-fluorophenyl)-5-methyl-N 1 -((R)-1,1,1-trifluoropropan-2-yl)-5,6-dihy droimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide 56
~ F~ -.
NN
56
In accordance with the synthetic route of Example 6, the starting compound 6a in Step 1 was replaced with the starting compound (S)-1-((4-methoxybenzyl)amino)propan-2-o (prepared according to the known method disclosed in "Organic and Biomolecular Chemistry, 2014, 12, 16, 2584-2591"), and the starting compound 2d in Step 4 was replaced with the starting compound 3d, accordingly, the title compound 56 (10 mg) was prepared. MS m/z (ESI): 439.2 [M+1]. 1H NMR (400 MHz, CD 30D) 6 7.88-7.86 (m, 1H), 7.83 (s, 1H), 7.76-7.72 (m, 1H), 7.33-7.28 (m, 1H), 5.16-5.11 (d, 1H), 5.03-4.98 (m, 1H), 4.85-4.81 (m, 2H), 4.04-4.00 (m, 1H), 3.72-3.66 (m, 1H), 1.60-1.56 (d, 3H), 1.44-1.42 (d, 3H).
Example 57 N5-(3-Cyano-4-fluorophenyl)-7-methyl-N 3-((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihydro
[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide 57
NC N iN H N
57
In accordance with the synthetic route of Example 39, the starting compound 6a in Step 1 was replaced with the starting compound 1-((4-methoxybenzyl)amino)propan-2-o (prepared according to the known method disclosed in "Organic and Biomolecular Chemistry, 2014, 12, 16, 2584-2591"), and the starting compound 2d in Step 5 was replaced with the starting compound 3d, accordingly, the title compound 57 (220 mg) was prepared. MS m/z (ESI): 440.2 [M+1]. 'H NMR (400 MHz, CD 30D) 6 7.85-7.87 (m, 1H), 7.72-7.75 (m, 1H), 7.28-7.33 (m, 1H), 5.01-5.06 (d, 1H), 5.16-5.21 (d, 1H), 4.80-4.81 (m, 2H), 4.13-4.17 (m, 1H), 3.75-3.80 (m, 1H), 1.69-1.70 (d, 3H), 1.18-1.21 (d, 3H).
Example 58 (S)-N7-(4-Fluoro-3-methylphenyl)-6-methyl-N 1 -((R)-1,1,1-trifluoropropan-2-yl)-5,6-dih ydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxamide58 F 0. H F
H3C N N'- NX H ,N N
58
In accordance with the synthetic route of Example 6, the starting compound 2d in Step 4 was replaced with the starting compound 4-fluoro-3-methylaniline (Shanghai Bide Pharmatech Ltd.), accordingly, the title compound 58 (14 mg) was prepared. MS m/z (ESI): 427.9 [M+1]. 1HNMR (400 MHz, CD 30D) 7.71 (s, 1H), 7.29-7.27 (m, 1H), 7.22-7.20 (m, 1H), 6.99-6.94 (m, 1H), 5.30-5.25 (d, 1H), 4.94-4.92 (m, 1H), 4.81-4.75 (m, 2H), 4.24-4.21 (m, 2H), 2.27-2.26 (d, 3H), 1.45-1.43 (d, 3H), 1.20-1.19 (d, 3H).
Example 59 (S)-N-(3,4-Difluorophenyl)-6-methyl-1-(pyrrolidine-1-carbonyl)-5,6-dihydroimidazo[1, 5-a]pyrazine-7(8H)-carboxamide 59 F 0 10 N3 F N N N H N
59
In accordance with the synthetic route of Example 11, the starting compound 3d in Step 1 was replaced with the compound 2d, the starting compound le in Step 3 was replaced with the starting compound pyrrolidine (Sinopharm Chemical Reagent Co.,
Ltd.), accordingly, the title compound 59 (10 mg) was prepared. MS m/z (ESI): 389.8 [M+1]. 'H NMR (400 MHz, CDCl 3) 6 7.69 (s, 1H), 7.52-7.47 (m, 1H), 7.20-7.16 (m, 3H), 5.26 (d, 1H), 4.93-4.90 (m, 1H), 4.77 (d, 1H), 4.23-4.21 (m, 2H), 4.04-4.01 (m, 2H), 3.63-3.60 (m, 2H), 2.01-1.93 (m, 4H), 1.22 (d, 3H).
Biological Assay Test Example 1. In vitro anti-HBV activity test of the compound of the present invention (quantitative assay of intracellular HBV DNA) I. Experimental materials and instruments 1. QIAamp 96 DNA QlAcube HT Kit (Qiagen) 2. QIAcube HT plasticware (Qiagen) 3. Hepatitis B virus nucleic acid quantitative detection kit (Triplex International Biosciences Co., Ltd.) 4. DNA extraction device (QlAcube) (Qiagen) 5. QuantStudio 6 Fiex (ABI, ThermFisher) 6. Microplate reader (BMG) 7. HepG2.2.15 cells (Shanghai Ruilu Biotechnology Co., Ltd.) II. Experimental procedures HepG2.2.15 cell is a stable expression cell line that has integrated HBV genome. Virus particles containing HBV DNA can be synthesized by replication, transcription and encapsidation in the cells, and then secreted. In this study, the quantitative analysis of HBV DNA produced by HepG2.2.15 in vitro proliferation was carried out by quantitative PCR method, thereby determining the activity of the compound of the present invention on inhibiting the HBV DNA replication by inhibiting the assembly of HBV capsid protein. HepG2.2.15 cells were cultured in DMEM/high glucose medium (10% FBS, 400
[tg/ml G418) and passaged every three days. On the day of the experiment, a cell suspension was prepared with fresh cell culture medium, and incubated in a 96-well plate (Corning, #3599) at 40,000 cells/well, at 5% carbon dioxide, 37°C. On Day 2, the compound was dissolved in pure DMSO at a concentration of 20 mM, and then the first concentration of 2 mM was formulated with DMSO, and and diluted in 4-fold concentration gradient to 8 concentrations. A control well was added with 90 1 of DMSO. The compound solution was diluted 200-fold with DMEM/high glucose medium. The cell culture plate inoculated on Day 1 was taken out. The medium in the wells was removed by a negative pressure suction device, and the formulated medium containing the compound at each concentration was added respectively to each well at 200 [/well. The plate was incubated at 37°C for 72 hours. On Day 5, the medium of the cultured cells was replaced with fresh medium containing the same compound in the same way as Day 2, and then the plate was incubated at 37°C for 72 hours. On Day 8, the cell culture plate was taken out, centrifuged at 300 g for 3 minutes, and the culture supernatant was collected at 200 [u/well. HBV DNA was extracted from the cell culture supernatant with Qiagen automatic DNA extraction device, and the specific method referred to the instructions of the reagents and instruments. Finally, the extracted DNA was eluted with DNA elution buffer at 100 [t/well. The extracted DNA was subjected to quantitative PCR analysis of HBV DNA using Hepatitis B virus nucleic acid quantitative detection kit (Triplex International Biosciences Co., Ltd.), and the specific method referred to the instruction of the kit. The quantitative standard curve was obtained with the standard sample provided in the kit, and the experiments were performed in parallel. Quantitative conversion of each sample was carried out according to the standard curve. Finally, the EC5 o value of the compound was calculated with Graphpad Prism software according to each concentration of the compound and the corresponding DNA value. Emax is the effect value of the compound to maximally inhibit HBV DNA replication. The in vitro activity of the compound of the present invention on inhibiting the HBV DNA replication by inhibiting the assembly of HBV capsid protein was determined by the above experiment. The measured EC5 o values are shown in Table 1. Table 1 EC5 o values of the compound of the present invention in the anti-HBV activity test (quantitative assay of intracellular HBV DNA) Example No. EC5 o (nM) Emax(%) 2 30 100 4 27 100 6 4 100 7 38 100 8 15 100 9 28 100 10 29 100 11 18 100 12 32 100 13 35 100 14 44 100 15 29 100 16 50 100 17 70 80 39 19 100 40 20 100 41 24 100 42 75 100 43 39 99 44 60 99 45 38 102
46 65 97 47 82 100 48 93 98 58 15 100 59 (Control Example) 5271 90 Conclusion: The compound of the present invention has a significant inhibition effect on HBV DNA replication, and has a significant advantage compared with Comparative Example 59. The main structural difference between Comparative Example 59 and the compound of the present application is that the amino group in the acylamino group is a tertiary amine, indicating that the secondary amino group in the acylamino group of the compound of the present application improves the biological activity significantly.
Test Example 2. Effect of the compound of the present invention on in vitro proliferation of HepG2 cells I. Experimental materials and instruments 1. HepG2 cells (ATCC) 2. CellTiter-GloTM Cell Proliferation Kit (Promega) 3. Automatic Pipetting Workstation (Bravo): Agilent Technologies Co. 4. Microplate reader (VICTOR 3): PerkinElmer Co. 5. CO 2 incubator (Fisher Scientific) 6. Centrifuge (Fisher Scientific) II. Experimental procedures HepG2 cells in logarithmic growth phase were taken and digested with trypsin to prepare a cell suspension, which was incubated in a 96-well plate (transparent bottom white 96-well plate, PerkinElmer) at 6,000 cells/well, at 5% carbon dioxide, 37°C for 16-20 hours. On Day 2, the compound was dissolved in pure DMSO at a concentration of 20 mM. The compound was diluted in 3-fold concentration gradient using an automatic pipetting station (Bravo), 8 concentration points for each compound, and the control well was DMSO. The compound formulated in DMSO at each concentration point was diluted 200-fold with EMEM (containing 10% FBS) medium. The cell culture plate inoculated on Day 1 was taken out. The medium in the wells was removed by a negative pressure suction device, and the formulated medium containing the compound at each concentration was added respectively to each well at 100 [u/well. The plate was incubated at 37°C for 72 hours. On Day 5, the 96-well cell culture plate was taken out, and freshly formulated CellTiter Glo was added to each well at 100 [u/well. The 96-well plate was left to stand for 5-10 minutes, the bottom was then sealed with a white bottom sealing film (PerkinElmer). The plate was placed in the microplate reader to measure the luminescence signal. The CC 5 o value of the compound was calculated with Graphpad Prism software according to each concentration of the compound and the corresponding proliferation inhibition signal value.
The inhibition effect of the compound of the present invention on in vitro proliferation of HepG2 cells was determined by the above experiment. The measured CC 5 o values are shown in Table 2. Table 2 CC5 o values of the compound of the present invention on in vitro proliferation inhibition of HepG2 cells Example No. CC 5o (PM) 2 >100 4 >100 6 >100 7 >100 8 >100 9 >100 10 >100 11 >100 12 >100 13 >100 14 >100 15 >100 16 >100 17 >100 39 >100 40 >100 41 >100 42 >100 43 >100 44 >100 45 >100 46 >100 47 >100 48 >100 58 >100 Conclusion: The compound of the present invention has no or little effect on the in vitro proliferation inhibition of HepG2 cells, and shows a high safety.
Pharmacokinetics Evaluation Test Example 3. Pharmacokinetics assay of the compound of the present invention 1. Abstract Rats were used as test animals. The drug concentration in plasma at different time points was determined by LC/MS/MS method after intragastrical administration of the compound of Example 1, the compound of Example 2, the compound of Example 4, the compound of Example 6, the compound of Example 7, the compound of Example 11, the compound of Example 39, the compound of Example 42, the compound of Example 44, the compound of Example 45 and the compound of Example 47 to rats. The pharmacokinetic behavior and property of the compound of the present invention were studied and evaluated in rats. 2. Test protocol 2.1 Test compounds Compound of Example 1, compound of Example 2, compound of Example 4, compound of Example 6, compound of Example 7, compound of Example 11, compound of Example 39, compound of Example 42, compound of Example 44, compound of Example 45 and compound of Example 47. 2.2 Test animals 44 Healthy adult SD rats (half male and half female, 4 rats/group) were purchased from Shanghai Jiesijie Laboratory Animal Co., LTD, with Certificate No.: SCXK (Shanghai) 2013-0006. 2.3 Preparation of the test compound A certain amount of the test compound was weighed, and added with 5% by volume of DMSO, 5% by volume of tween 80 and 90% by volume of normal saline to prepare a 0.2 mg/mL colorless, clear and transparent solution. 2.4 Administration After an overnight fast, SD rats were administrated intragastrically with the test compound at an administration dose of 2.0 mg/kg and an administration volume of 10.0 mL/kg. 3. Process The rats were intragastrically administrated the compound of Example 1, the compound of Example 2, the compound of Example 4, the compound of Example 6, the compound of Example 7, the compound of Example 11, the compound of Example 39, the compound of Example 42, the compound of Example 44, the compound of Example 45 and the compound of Example 47. 0.1 ml of blood was taken from the orbit before administration and at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0 and 24.0 hours after administration. The samples were stored in heparinized tubes, and centrifuged for 10 minutes at 3500 rpm to separate the blood plasma. The plasma samples were stored at -20°C. The rats were fed two hours after administration. The content of the test compound in the plasma of rats after intragastrical administration of the test compound at different concentrations was determined: 25 L of rat plasma at each time after administration was taken, added with 40 L of the internal standard solution of camptothecin (100 ng/mL) and 200 L of acetonitrile, vortex-mixed for 5 minutes, and centrifuged for 10 minutes (4000 rpm). 0.2 L of the supernatant was taken from the plasma samples for LC/MS/MS analysis. 4. Results of pharmacokinetic parameters Pharmacokinetic parameters of the compound of the present invention are shown below: Pharmacokinetics assay (2 mg/kg)
Residence Apparent Bioavail Plasma Area under No. concentration curve Half-life Clearance distribution ability( volume %) Cmax AUC T1/2 MRT CLz/F Vz/F F% (ng /mL) (ng /mL*h) (h) (h) (ml/min/kg) (ml/kg) Example 1 640±102 14438±3012 11.7±2.3 17.4±3.0 2.39±0.5 2357±245 119
Example 2 661±200 9251±3309 8.01±2.26 11.5±2.8 4±1.48 2584±638 107
Example 4 425±100 7129±2636 8.8±1.95 13.1±2.5 5.08±1.48 3692±532 120
Example 6 629±167 12920±6605 10.8±8.1 16.7±10.1 3.22±1.66 2162±721 120
Example 7 1078±151 16528±9264 9.72±5.94 14.1±8.0 2.63±1.46 1649±174 98
Example 11 597±64 10870±4522 11.2±5.63 16.3±7.6 3.53±1.50 2888±389 111
Example 39 682±168 8105±1585 6.49±1.71 9.82±1.75 4.21±0.69 2328±590 114
Example 42 433±102 7380±3177 15.9±8.9 22.1±12.4 5.3±2.47 5962±1222 87
Example 44 509±39.4 11771±3103 17±5.05 24.2±7.38 2.99±0.78 4134±260 94
Example 45 715±187 17162±5791 19.2±7.16 27.4±9.5 2.13±0.73 3293±1078 110
Example 47 462±94 7265±3054 13.1±4.3 17.7±6.3 5.4±2.69 5685±2240 125
Conclusion: The compound of the present invention is well absorbed, and has a high bioavailability and pharmacokinetic advantage.

Claims (17)

WHAT IS CLAIMED IS:
1. A compound of formula (I): R2 0
(R4)N R1 (R ~ / N _
/ (R 3) n H I
) or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: ring A is aryl or heteroaryl; Y is N or CR5 ; Q is N or CH; R 1 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted by one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 , -C(O)OR 6 and -S(O)mR6 ; R2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted by one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R, -C(O)OR 6 and -S(O)mR6 ; each R3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6, -C(O)R6 ,
-C(O)OR6 and -S(O)mR6; each R4 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 ,
-C(O)OR6 and -S(O)mR6; R 5 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R6 is selected from the group consisting of hydrogen, alkyl, haloalkyl, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is 0, 1, 2 or 3; m is 0, 1 or 2; and s is 0, 1, 2, 3 or 4.
2. The compound of formula (I) according to claim 1, being a compound of formula (II): O H 0 N1. N R1 R4) C I H N ,Y (R
) (11) wherein: ring A, Y, Q, R', R, R4, s and n are as defined in claim 1.
3. The compound of formula (I) according to claim 1 or 2, being a compound of formula (III), formula (IV), formula (V) or formula (VI): O H O H 0 N" 0 N1. A4)A N JN R1 (4s N)N R1 (3 H N R4 H /NN N NN (R 3)n (R 3)"
(111) (IV )
O H O H 0 Nl 0 NI A R1 R1 (4) R 4)NN H(R )N H /
(R 3 )"
(V) (VI) wherein: ring A, R, R 3, R 4, s and n are as defined in claim 1.
4. The compound of formula (I) according to any one of claims I to 3, wherein ring A is phenyl or pyridyl.
5. The compound of formula (I) according to any one of claims 1 to 4, being a compound of formula (VII), formula (VIII), formula (IX) or formula (X):
O H O H
(R4) N N R1 (R)a N N R H N H N N (R3)II (R3)I
(VII) (ViII) O H O H 0N G0 N (R 4 )- NR1 (R 4)N R NNN N Hr N N H N_" H LN/ 3 (R3 (R )I
(IX) (X) wherein: GisC orN; and R , R , R 4, s and n are as defined in claim 1.
6. The compound of formula (I) according to any one of claims 1 to 5, wherein R is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl and aryl, wherein the alkyl, cycloalkyl, heterocyclyl and aryl are optionally further substituted by one or more substituents selected from the group consisting of halogen, alkyl, alkoxy and hydroxy.
7. The compound of formula (I) according to any one of claims 1 to 6, being a compound of formula (VII-A), formula (VIII-A), formula (IX-A) or formula (X-A): 0OH 0OH (R)~IN G 0 N R (R4)s N N 4 NR NNR 8 H H / R R 3 NN R8 R3 N N R
(VII-A) (Vill-A)
(R 4 )S N N N N H N R8 H 3 R N!/ R3 N'N RHR
( IX-A) (X-A) wherein: G is C or N; R8 is alkyl, preferably methyl; R9 is alkyl, wherein the alkyl is optionally further substituted by one or more halogen; and R3, R 4, s and n are as defined in claim 1.
8. The compound of formula accordingg to any one of claims Ito 7,whereinR 3 is hydrogen or alkyl.
9. The compound of formula accordingg to any one of claims Ito 8,whereinR 4 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl and cyano.
10. The compound of formula ()according to any one of claims Ito 9,selected from the group consisting of:. F F. 0 HN F 0 H F F ~ 0 F N~N ~t F 0~~' -f' F H NH HNN
12 3
F H F F0H F IF OH' F F)::N 0N F:N 0 N rF F NN0 H ',H "'N r H AN , N-.N' N-~ 4 5 6 F0 HLF F0 0 H 0 N'F 51,N F 0 H IF FNNN H F N F 0 F a H .C N -NN N F " N_ N
FF F H FO N F N N F 0 N\F "F N)a H F N NH
13
1 1 F FF F H F 0F F 0 H F
FNN J 0. N F 0~ - NF
F F
FNIb> N N NtJ~. H N -//NN0 W H NN'
1519 20 215 FF FHO O H N F . N NNF F~ N~
H N_ H 'N H '0 N ,
12 2 7 24
F 108
F H F F 0~ O F 0 H FO N"' N.4F F N~ N][N Nn) H I _ H I" N-/ N F H _ ~ N-N ~N 25 26 27
F. F NN 0OH N F rN 0N FrO 0 HHF NF F FNN 0 F 0 KHC H Nr' H KN i'H 0
28 29 30 F F
N H F F ' 0~ H H 0N H N H 0 NN N-N NFj ~
31 32 33 F F . HOH F 0 0N F
Fa N <- O NI Fa I],0_ 0H N! CNN/N- 0
34 35 36
o H F F OH N.Q L-F F N NN HF
F_ - F F N a F HF F H
NN H- _ FN H - N N F
FF 0 H F 0N F OH1
H N NNN N H Y ~N ,
N -, -NHy NN
43 44 4 5
F0 H F .F 0 H F F
F-o NNN N KN N /N H W'N- H _N N N
46 47 48
F 0 H F O H F OH N - 0 -NH %F- N 0 N , - N F N N HCFC XN~~ H H "N H _N
49 0 51
F N FF F 0H FN F H N F H N F N N H N F N ' I F NC a NN N> 3C~ N/ H N/0 NN, N 52 53 54 F51. 0 H F F 0 O
Ha N N F' OH F
3 N
/ H HN F~
0 ORa 4 (R )r y^N
(R3 ),
( IA )
or atautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or apharmaceutically acceptable salt thereof, wherein: 3R3)
Raishydrogenor alkyl; ring Ais aryl or heteroaryl; Y is Nor CR 5; Q is N or CH; eachRisidentical differentand eachisindependentlyselectedfromthegroup consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 ,-C(O)R, -C(O)OR andS(O)mRandpreferably hydrogen oralkyl; each R4 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6, -C(O)R6 ,
-C(O)OR6 and -S(O)mR6; R5 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R6 is selected from the group consisting of hydrogen, alkyl, haloalkyl, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is0, 1, 2or 3; m is0, 1or 2;and s is0, 1, 2, 3or4.
12. The compound of formula (IA) according to claim 11, selected from the group consisting of: F F 0 0
F)KaN NI F& N N -)IN H N_/ H N / N.~ F): H KN' N
id 2e 4a F0 0 0 000 F1 0 0\ F NF H N H N H N N , N N N
5b 6f 7e
0OH F ~ 0F 0 OH
\\:: ' NN. H NN If 9a N bN
F F
F Fk OH F.
NN I: Nr_ _N \\\ N. N
10a 10b 11a
011 0OH F. OH
H N N' F--- N0 -\ F N \\ NH NH KN,//N 11b 13a 13b F F
0 0OH F 0 OOH F ~O 0 N N -a
H N H N_/ F H N-~ 17e 19a 37c and Fa 00 OH
NN N HN
45d
13. Acompound of formula (111A):
OH N 'RR' (Mt- HN - W N,/N (R3 )" (lilA) or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: M is trifluoroacetic acid or hydrochloric acid; R 1 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted by one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 , -C(O)OR 6 and -S(O)mR6 ; each R3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6, -C(O)R6
, -C(O)OR6 and -S(O)mR 6 , and preferably hydrogen or alkyl; tis0or 1; and n is 0, 1, 2 or 3.
14. A compound selected from the group consisting of: o 0 0 OHN FF NI F F F N F OH HN F OHHW 4F F ') O N HN N FO N
3c N 15c
0OH F
HN N and \\" NN
15. A method for preparing the compound of formula (I) according to claim 1, comprising a step of:
0 OR a H"R N/ 4) A NJN HNNR1 A NN ), NR (R) H O ( IBH (R 4 ), RN S H AI (Rs (R
( IA) (I) reacting a compound of formula (IA) with a compound of formula (IB) or a salt thereof to obtain the compound of formula (I), wherein: Ra is hydrogen or alkyl; each R' is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R, -C(O)OR6and -S(O)mR, and preferably hydrogen or alkyl; and ring A, Y, Q, R', R, R4, s and n are as defined in claim 1.
16. A method for preparing the compound of formula (II) according to claim 2, comprising a step of: 0 0H 0 ORa 0 -N' (R4) O H2N-R1 (R 4) A NN R1 SH N / (11B) (RY (R3
) (IA) (II) reacting a compound of formula (IA) with a compound of formula (JIB) or a salt thereof to obtain the compound of formula (II), wherein: Ra is hydrogen or alkyl; each Ris identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R, -C(O)OR6and -S(O)mR, and preferably hydrogen or alkyl; and ring A, Y, Q, R1, R4, s and n are as defined in claim 1.
17. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of formula (I) according to any one of claims 1 to 10, and one or more pharmaceutically acceptable carrier(s), diluent(s) or excipient(s).
18. Use of the compound of formula (I) according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 17 in the preparation of a capsid protein inhibitor.
19. Use of the compound of formula (I) according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating a viral infection disease, wherein the virus is preferably selected from the group consisting of hepatitis B virus, influenza virus, herpes virus and AIDS virus, and the diseases is preferably selected from the group consisting of hepatitis B, influenza, herpes and AIDS.
WHAT IS CLAIMED IS:
1. A compound of formula (I): R2 0 N N N~N ~ 'R1 H K N /9Y (R))
or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: ring A is aryl or heteroaryl; Y is N or CR 5; Q is N or CH; R' is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted by one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6 , -C(O)R 6, -C(O)OR 6 and -S(O)mR 6; R2 is hydrogen; each R3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6, -C(O)R 6 , -C(O)OR 6 and -S(O)mR 6; each R4 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6, -C(O)R 6 ,
-C(O)OR 6 and -S(O)mR 6; R5 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl; R 6 is selected from the group consisting of hydrogen, alkyl, haloalkyl, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is 0, 1, 2 or 3; m is 0, 1 or 2; and s is 0, 1, 2, 3 or 4.
2. The compound of formula (I) according to claim 1, being a compound of formula (III), formula (IV), formula (V) or formula (VI):
O H O H 0 N 0 N
R1 A NN NR1 (NN N NN (R3 ),
(111) (IV
) O H O H 0 N 0 N
(R4)- R1 (R), ) R1 H Y-1N,-, "N "R (R 5 ') H NK/~N~N~ (R 3)n R)n
(V) (VI) wherein: ring A, R', R, R 4, s and n are as defined in claim 1.
3. The compound of formula (I) according to claim 1 or 2, wherein ring A is phenyl or pyridyl.
4. The compound of formula (I) according to any one of claims 1 to 3, being a compound of formula (VII), formula (VIII), formula (IX) or formula (X): O H O r"0H G 0 N ( NN R1 (R4)- N N Ri
H (R3 N/N H(R N'
(V11) 01N 0 (VIII) N
OH OH ()n (R)n (R4) N N(NRR1 (R4) N N N Ri H LN..,N HN/
(IX) (X) wherein: G isC or N;and RR 3 ,Rs andnare asdefined inclaim1.
5. The compound of formula (I) according to any one of claims 1to 4,wherein R is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl and aryl, wherein the alkyl, cycloalkyl, heterocyclyl and aryl are optionally further substituted by one or more substituents selected from the group consisting of halogen, alkyl, alkoxy and hydroxy.
6. The compound of formula (I) according to any one of claims 1 to 5, being a compound of formula (VII-A), formula (VIII-A), formula (IX-A) or formula (X-A): 0OH O H 9 ( (R)I N (R) N 0 NR N, R (R4) 'f H R8 H N N R8
R 3 R3 N
(VII-A) (VIII-A)
N N) N R9 (R 4) N N R9 H 3N R8 H 3 R8 HR N/ R3 N R
(IX-A) (X-A)
wherein: G is C or N; R is alkyl, preferably methyl; R9 is alkyl, wherein the alkyl is optionally further substituted by one or more halogen; and R3, R4 and s are as defined in claim 1.
7. The compound of formula (I) according to any one of claims 1 to 6, wherein R3 is hydrogen or alkyl.
8. The compound of formula (I) according to any one of claims 1 to 7, wherein R4 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl and cyano.
9. The compound of formula (I) according to any one of claims 1 to 8, selected from the group consisting of: F F 0 H F
F N0N F F NNN FNN F H N FN HN F F 1 2 3
F N N F F N 'NF N N F F0HH 0 H F 0 HF H KH N 4N H NJN
4 5 6 H HH KN 71.- ,8I9 N F N N H / N 10 N NAN
F
N F 0 H FF 0 H F~~N~0 N,~ H:& N N N-/ '~~
' 10 11 12 F F F O H F O H F 0 H F
ILH F, 0 HF N"ZN 0Y. H 0 N F,,,, - JF FNNF F ~N F
16 17 18 F F F F OH OHFF0 HOH FN~N- N~ N 0 NH F
OH F F:b ON I FoN~ _r H~1 N_/ N H /r F H H ~~.. N N
FF F F0 F 0 HF F0 H 0N~. N J N F N OH
cH KN ' H KN 4 H _N I~ 25 2 6 27
F OH F-s N/F F 0 H
, F 0 FNN 0 N F Fr N -a %- FN N~ )'F N ,rN
F C4 OH CFL F ~ Na
N F F.N FQ 4 O H~N F F~
34 35 36
F 0 H F O H F F O H 1I1 N_ F N1 \ F F N~N ~ F " N N'- %F- F~'N N H I N H NH N_ F QN,N N F 37 38 39 F FF NH F 0 HH
:)Fk 1 F-K ' \FHN N.FN N N HiN~ - F- N N -FKN-
" HHN H I N ,,. , - ,, -.
, 40 41 42 F O H F F ~ 0
F~ F~- ~ cNNNkF NN-N N'NN - [F F~ o N'' ~ 4F H< ~ N N, H 'I
43 44 45
F 0 F ~ 0
r J NH NN-~& N ~ H K.N. 4 NNN
46 47 48 F 0 H F F O H F O H 0N FF 0 N ~ iN FaNN N VN NC NaN W -
NCN H ,N N N H H 3C
49 50 51
0 0 H F HF<~ F~
N NN N^'IXFF~cNN - 4~>~ FF H H -F Ca! 4 H~. FAN.N H3c.-
52 53 54 F ~ 0 H F F 0 H 0 F N'N ~ F -N J~ ~ - ~ _F F
N~F r 3 HN N N
and 585
10. Acompound of formula (IA):
0 ORa
4) (RSHN NI /Y 3N" (R ).
(IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Ra is hydrogen or alkyl; ring A is aryl or heteroaryl; Y is N or CR 5; Q is N or CH; each R3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R 6 , -C(O)0R 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; each R4 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6, -C(O)R 6
, -C(O)OR 6 and -S(O)mR 6; R5 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl; R 6 is selected from the group consisting of hydrogen, alkyl, haloalkyl, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is 0, 1, 2 or 3; m is 0, 1 or 2; and s is 0, 1, 2, 3 or 4.
11. The compound of formula (IA) according to claim 10, selected from the group consisting of: F F F. 00F0 F 0 0 0
F FN),NX NN O F NH 'NC N - O F FI N 1NNO H N /N N- N H KN~N
1d 2e 4a
F 0 0 0 0 0 F0 00O F- N N HFNNN O F NN H N H NN H
5b 6f 7e
FO OH F O 0 N 0 OH
if 9a 9b F N)N O F N O N NN O F N N F N'N . N_ F N O F N N O F N 0 10a 10b 11a
NN H KN' H N H N
11a 1b 13a
F F O0 0H F ~ 00 F ~ 0O
NN OHF N OH F NN H N N H , HN H NN
1b 13a 13b F F F o F 00 _ _OH 0 OH N 1 O0 FN N -- F NN N H HNN/ F
1e 19a 37c and N N OH 0 OH -r 'N Na N X N H _N
45d 0N
12. Acompound of formula (111A): O H N
(M)t- HN NN (R3)Y.-N ( llA) or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: M is trifluoroacetic acid or hydrochloric acid; R' is alkyl which is further substituted by one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR6 , -C(O)R6 ,
-C(O)OR 6 and -S(O)mR 6; or R' is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted by one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6 , -C(O)R 6, -C(O)OR 6 and -S(O)mR 6; each R3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6, -C(O)R 6
, -C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; R6 is selected from the group consisting of hydrogen, alkyl, haloalkyl, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; m is 0, 1 or 2; tis0or 1; and n is 0, 1, 2 or 3.
13. A compound selected from the group consisting of: HF 0 F N4FF
HN N F OH HN F
3c N~ 15c O H F
HN F N' andV N\N
14. A method for preparing the compound of formula (I) according to claim 1, comprising a step of:
SORa HN (R4) :A NNN R - R1 A N NRI (R) H N(/Y IB) 4)N HR
(IA) (I) reacting a compound of formula (IA) with a compound of formula (IB) or a salt thereof to obtain the compound of formula (I), wherein: Ra is hydrogen or alkyl; each R3 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6, -C(O)R 6 ,
-C(O)OR 6 and -S(O)mR 6 , and preferably hydrogen or alkyl; and ring A, Y, Q, R', R, R4, R6, m, s and n are as defined in claim 1.
15. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of formula (I) according to any one of claims 1 to 9, and one or more pharmaceutically acceptable carrier(s), diluent(s) or excipient(s).
16. Use of the compound of formula (I) according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 15 in the preparation of a capsid protein inhibitor.
17. Use of the compound of formula (I) according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating a viral infection disease, wherein the virus is preferably selected from the group consisting of hepatitis B virus, influenza virus, herpes virus and AIDS virus, and the diseases is preferably selected from the group consisting of hepatitis B, influenza, herpes and AIDS.
AU2018305614A 2017-07-27 2018-07-26 Piperazine heteroaryl derivative, preparation method therefor and use of same in medicine Ceased AU2018305614B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
CN201710621744 2017-07-27
CN201710621744.9 2017-07-27
CN201711058986.8 2017-11-01
CN201711058986 2017-11-01
PCT/CN2018/097170 WO2019020070A1 (en) 2017-07-27 2018-07-26 Piperazine heteroaryl derivative, preparation method therefor and use of same in medicine

Publications (2)

Publication Number Publication Date
AU2018305614A1 AU2018305614A1 (en) 2020-03-05
AU2018305614B2 true AU2018305614B2 (en) 2022-05-12

Family

ID=65040957

Family Applications (1)

Application Number Title Priority Date Filing Date
AU2018305614A Ceased AU2018305614B2 (en) 2017-07-27 2018-07-26 Piperazine heteroaryl derivative, preparation method therefor and use of same in medicine

Country Status (11)

Country Link
US (1) US11247998B2 (en)
EP (1) EP3660018A4 (en)
JP (1) JP2020528062A (en)
KR (1) KR20200032702A (en)
CN (1) CN109952305B (en)
AU (1) AU2018305614B2 (en)
BR (1) BR112020001299A2 (en)
CA (1) CA3070004A1 (en)
RU (1) RU2745431C1 (en)
WO (1) WO2019020070A1 (en)
ZA (1) ZA201908609B (en)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR117188A1 (en) * 2018-11-02 2021-07-21 Aicuris Gmbh & Co Kg DERIVATIVES OF UREA 6,7-DIHIDRO-4H-PIRAZOLO [1,5-A] PYRAZINES ACTIVE AGAINST THE VIRUS OF HEPATITIS B (HBV)
AR116947A1 (en) * 2018-11-02 2021-06-30 Aicuris Gmbh & Co Kg DERIVATIVES OF UREA 6,7-DIHIDRO-4H-PIRAZOLO [1,5-A] PIRAZINAS-INDOL-2-CARBOXAMIDAS ACTIVE AGAINST THE VIRUS OF HEPATITIS B (HBV)
JP2022523035A (en) * 2019-01-25 2022-04-21 江▲蘇▼恒瑞医▲薬▼股▲フン▼有限公司 1,2,3-Triazolo [1,5-a] Pyrazine derivative crystal form and method for preparing the crystal form
CN111484498B (en) * 2019-01-25 2021-05-14 江苏恒瑞医药股份有限公司 Crystal form of imidazo [1,5-a ] pyrazine compound and preparation method thereof
CN111484497B (en) * 2019-01-25 2021-07-02 江苏恒瑞医药股份有限公司 Pharmaceutical salt and crystal form of imidazo [1,5-a ] pyrazine derivative and preparation method thereof
AU2020265390A1 (en) 2019-04-30 2021-12-23 Aicuris Gmbh & Co. Kg Novel phenyl and pyridyl ureas active against the hepatitis B virus (HBV)
CA3138385A1 (en) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Novel indolizine-2-carboxamides active against the hepatitis b virus (hbv)
JP2022530522A (en) 2019-04-30 2022-06-29 アイクリス ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト A novel indole-2-carboxamide that is active against hepatitis B virus (HBV)
WO2020221811A1 (en) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Novel oxalyl piperazines active against the hepatitis b virus (hbv)
CN112778299B (en) * 2019-11-04 2023-07-14 江苏恒瑞医药股份有限公司 Piperazine ureido derivatives, preparation method thereof and application thereof in medicines
TW202214658A (en) * 2020-07-29 2022-04-16 大陸商江蘇恒瑞醫藥股份有限公司 Preparation method and application of triazolo[1,5-a]pyrazine
CN114057745A (en) * 2020-07-29 2022-02-18 江苏恒瑞医药股份有限公司 Preparation method and application of triazolo [1,5-a ] pyrazine
AU2021360496A1 (en) * 2020-10-15 2023-05-04 Aligos Therapeutics, Inc. Bicyclic compounds
WO2022166778A1 (en) * 2021-02-04 2022-08-11 江苏恒瑞医药股份有限公司 A pharmaceutical composition of a capsid protein inhibitor and preparation method thereof
CN114146582A (en) * 2021-11-30 2022-03-08 南京工业大学 Preparation method of fluorinated ZIF-90 modified PDMS membrane

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150133428A1 (en) * 2013-11-14 2015-05-14 Bristol-Myers Squibb Company Novel substituted pyrazolo-piperazines as casein kinase 1 d/e inhibitors

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10012824A1 (en) 2000-03-16 2001-09-20 Bayer Ag New 6-hydroxyhydrocarbyl or 6-thiohydrocarbyl-dihydropyrimidine-5-carboxylic acid derivatives, useful for the treatment of viral infections, especially hepatitis B infections
NZ531378A (en) * 2001-09-19 2006-11-30 Aventis Pharma S Indolizines as kinase protein inhibitors suitable for treating solid tumours
AU2008226649B2 (en) * 2007-03-09 2013-08-01 Sanofi Substituted dihydro and tetrahydro oxazolopyrimidinones, preparation and use thereof
EA201000046A1 (en) * 2007-06-21 2011-02-28 Кара Терапеутикс, Инк. SUBSTITUTED IMIDASOGETEROCYCLES
US8859538B2 (en) 2007-06-21 2014-10-14 Cara Therapeutics, Inc. Uses of substituted imidazoheterocycles
FR2960876B1 (en) * 2010-06-03 2012-07-27 Sanofi Aventis 3,4-DIHYDROPYRROLO [1,2-A] PYRAZINE-2,8 (1H) -DICARBOXAMIDE DERIVATIVES FOR THEIR PREPARATION AND THEIR THERAPEUTIC USE.
GB201010422D0 (en) 2010-06-22 2010-08-04 Univ Cardiff Cartilage repair
CN102464661B (en) 2010-11-16 2015-04-01 天津药明康德新药开发有限公司 Preparation method of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester
FR2986002B1 (en) 2012-01-24 2014-02-21 Servier Lab NOVEL INDOLIZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
CN103626752B (en) 2012-08-24 2015-08-12 广东东阳光药业有限公司 Dihydropyrimidines and the application in medicine thereof
CN102875270B (en) 2012-09-24 2014-12-03 巨化集团公司 Method for synthesizing trifluoromethyl amine
HUE039152T2 (en) 2013-07-25 2018-12-28 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
AP2016009257A0 (en) 2014-02-06 2016-06-30 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
AR101319A1 (en) 2014-07-31 2016-12-07 Hoffmann La Roche QUIRAL RESOLUTION OF THE ESTERS OF THE ACID 4-ARIL-2-TIAZOL-2-IL-1,4-DIHYDROPIRIMIDIN-5-CARBOXYL
MA41338B1 (en) * 2015-01-16 2019-07-31 Hoffmann La Roche Pyrazine compounds for the treatment of infectious diseases
BR112018009009A8 (en) 2015-11-03 2019-02-26 Hoffmann La Roche combined therapy of an hbv capsid formation inhibitor and an interferon
EP3458455B1 (en) 2016-05-20 2021-06-16 F. Hoffmann-La Roche AG Novel pyrazine compounds with oxygen, sulfur and nitrogen linker for the treatment of infectious diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150133428A1 (en) * 2013-11-14 2015-05-14 Bristol-Myers Squibb Company Novel substituted pyrazolo-piperazines as casein kinase 1 d/e inhibitors
US20160311824A1 (en) * 2013-11-14 2016-10-27 Bristol-Myers Squibb Company Substituted 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine derivatives as casein kinase 1 d/e inhibitors

Also Published As

Publication number Publication date
US20200157111A1 (en) 2020-05-21
EP3660018A4 (en) 2021-04-21
BR112020001299A2 (en) 2020-07-28
WO2019020070A1 (en) 2019-01-31
AU2018305614A1 (en) 2020-03-05
JP2020528062A (en) 2020-09-17
CN109952305A (en) 2019-06-28
US11247998B2 (en) 2022-02-15
RU2745431C1 (en) 2021-03-25
CA3070004A1 (en) 2019-01-31
KR20200032702A (en) 2020-03-26
ZA201908609B (en) 2022-07-27
EP3660018A1 (en) 2020-06-03
CN109952305B (en) 2022-06-21

Similar Documents

Publication Publication Date Title
AU2018305614B2 (en) Piperazine heteroaryl derivative, preparation method therefor and use of same in medicine
JP6684552B2 (en) Pyrazolo [1,5-a] pyrimidines as antiviral agents
AU2014256633B2 (en) Fused heterocyclic compounds as protein kinase inhibitors
ES2539257T3 (en) Imidazo [1,2-b] substituted pyridazines
AU2011256380B2 (en) Macrocyclic compounds as Trk kinase inhibitors
CN113185519A (en) Nucleoside compound and application thereof in treating feline infectious peritonitis
CN110945000B (en) Macrocyclic compounds containing aminopyrazolopyrimidines, pharmaceutical compositions and uses thereof
AU2013239816A1 (en) Lactam kinase inhibitors
EP3402789B1 (en) Isoquinolones as btk inhibitors
CN114765979A (en) Nucleoside compound and application thereof in treating feline infectious peritonitis
CN113527299A (en) Nitrogen-containing condensed ring compounds, preparation method and application
ES2416062T3 (en) Indolobenzadiazepine HCV NS5B inhibitors fused to pyrrolidine
EP2953461B1 (en) Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c
EP4206199A1 (en) Aromatic ring-lactam compound, preparation method therefor and use thereof
CA2873898A1 (en) Hepatitis c inhibitor compounds
CA2821777A1 (en) Substituted pyrimido[1,2-b]indazoles and their use as modulators of the pi3k/akt pathway
JP5987255B2 (en) Hepatitis C inhibitor compound
TW201910333A (en) Piperazine-heteroaryl derivative, preparation method thereof and application thereof in medicine
TWI602818B (en) Fused heterocyclic compounds as protein kinase inhibitors
CN117813309A (en) Compounds as immunomodulators for PD-L1 interactions
OA16278A (en) Pyrazolo [1,5-A] pyrimidines as antiviral agents.
AU2015200638A1 (en) Pyrazolo [1, 5 -a] pyrimidines as antiviral agents

Legal Events

Date Code Title Description
FGA Letters patent sealed or granted (standard patent)
MK14 Patent ceased section 143(a) (annual fees not paid) or expired